Macrophage recruitment and proliferation of both small vessels (endothelium and pericytes) and fibroblast-myofibroblasts are the fundamental and provisional cellular findings in repair through granulation tissue (RTGT).Endothelium and pericytes of preexisting microvasculature may act as progenitor cells of new endothelial cells and new pericyte-fibroblast-myofibroblasts, respectively.Likewise, fibroblasts may be progenitors of themselves, and of myofibroblasts and pericytes. Moreover, all these cells may originate from circulating progenitor cells or other progenitor cells..According to this extensive cellular plasticity, this work reviews the adult stem cells (ASC) and transit- amplifying cells (TAC) related to the principal cellular components of RTGT.Moreover, we hypothesize that the perivascular region, with a heterogeneous pericyte-like cellular population, including pericytes, perivascular fibroblasts and homing cells from the bone marrow (fibrocytes and bone marrow mesenchymal cells), is the niche of progenitor cells in RTGT and the substrate of regulatory mechanisms (perivascular niche hypothesis).We also highlight RTGT as a "paracrine transitional organ" during involutive phenomena and cellular differentiation.Furthermore, we consider the combined role of both systems (ASC-TAC and RTGT) in tissue engineering and in pathological processes, such as fibrosis, organization, atherosclerosis, and tumor stroma.

2. INTRODUCTION

2.1. ASC and TAC

Under normal physiologic conditions, the lost cells are replaced by means of a system comprising adult stem cells (ASC) and transit-amplifying cells (TAC), as well as the ASC niches, with their intrinsic and extrinsic regulatory mechanisms.ASC, able to self renew and to intervene in maintaining the structural and functional integrity of their original tissue, can express greater plasticity than traditionally attributed to them (1-5), adopting functional phenotypes and expression profiles of cells from other tissues (3, 4, 6-22).TAC are committed progenitors among the ASC and their terminally differentiated daughter cells.TAC, with more rapid though limited proliferation, low self-renewal and restricted differentiation, increase the number of differentiated cells produced by one ASC division.The ASC and TAC are located in one place, or structural unit (structural proliferative unit, for instance, the intestinal crypt).The ASC, in particular reside in a specialised physical location (for instance, between and immediately above Paneth cells in the small intestine crypt - 23), named niche (24-29), which constitutes a three-dimensional microenvironment where they are protected and controlled in their self-renewing capacity and differentiation.Cell contacts with neighbouring cells (adherens junctions - cadherins and catenins) and with extracellular matrix (basal membrane - integrins), and the balance of stimulatory and inhibitory signals that regulate cell quiescence (epidermal and basic fibroblast growth factors, mytogenic cytokines and WNTS signaling, BMP/TGFβ) participate in this regulatory mechanism (30-36).

2.2. Repair through granulation tissue

After injury, ASC intervene in the replacement of damaged or dead cells with new healthy cells using reparative mechanisms.Classically, from a broad perspective, repair includes two types of processes: regeneration and repair through granulation tissue (RTGT).Both types of repair processes use similar mechanisms and, to a greater or lesser extent, appear combined.Regeneration occurs when dead, degenerated or damaged cells are replaced by other cells of the same type.Related to this form of repair are metaplasia (replaced by another different adult cell type) and dysplasia (replaced by cells that undergo atypical cytologic changes in their organisation, shape and size).By means of this procedure, the parenchymal cells of the tissues may be replaced in normal or pathological conditions.RTGT occurs by definition through granulation tissue: a provisional tissue with macrophage recruitment and proliferation of small blood vessels and fibroblasts-myofibroblasts.During RTGT, the following findings may occur: a) perfect reconstruction of the original tissue stroma, parallel to the regeneration of parenchymal elements; b) stroma formation of proliferative elements different to the original parenchyma, such as tumor stroma; c) total or partial replacement of the specialized parenchymal elements by permanent nonspecialized fibrous tissue (scarring); d) creation of new masses of fibrous tissue in blood clots or inflammatory exudates with fibrin deposits, by a process referred to as organization; and e) formation of other tissues, such as bone, cartilage and adipose.

2.3. ASC and TAC in RTGT

The role of ASC and TAC in regeneration has been widely treated in several excellent original and review articles, while the role of these cells in RTGT has principally been considered separately in the various events of the latter.Since the formation of supporting stroma and/or of some tissues (bone, cartilage, adipose) from ASC can require similar mechanisms in tissue engineering to those in RTGT, an overall correlation of both systems, with a comprehensive review in this field (ASC in RTGT), is of interest.Furthermore, this would help to understand several RTGT-related pathological processes, such as thrombus organization, neoplasm growth and atherosclerosis.Given the above, the object of this article is to review the role, nature, location (niches) and regulatory systems of ASC and TAC that intervene in RTGT, and in its derived pathological processes.

3. REGIONS WITH RTGT CAPACITY

The regions with RTGT capacity are the most ubiquitous in all repair.However, they have a common characteristic: the presence, in or near, of an active preexisting pericytic microvasculature, where the repair phenomena initiate.The latter originate above all in the venous side of the circulation, specifically in the postcapillary venules (37, 38).Therefore, this microvasculature forms part of a substrate of a general inflammatory-reparative system in which the vessels not only intervene in recruitment of inflammatory cells and in new capillary formation (angiogenesis), but they may also contribute matrix-forming cells (fibroblasts-myofibroblasts, osteoblasts, chondroblasts), and contractile and adipose cells.Vessels of greater caliber in the circulation, such as the rat femoral vein, with a discontinuous internal elastic lamina and smooth muscle cells in their media layer, are also capable of contributing to RTGT (39-42).

The RTGT capacity of the regions has biological and clinical implications.In avascular tissues (e.g.cartilage and cornea), there is capacity of regeneration, but RTGT may only originate from neighbouring vascularized tissues.In this case, the intensity of RTGT component penetration into an avascular tissue depends on the properties of the latter (e.g.inhibitory action of antiangiogenic substances, as occurs in cartilage).In addition, the RTGT characteristics of a region may be conditioned by its regenerative capacity (interactions between regeneration and RTGT).For instance, in the central nervous system and cardiac muscle, where the regeneration is limited, the RTGT local precursor cells are generally involved in scar tissue replacement.

4. EVENTS IN RTGT

RTGT is a complex biological process that involves coagulation, inflammation, angiogenesis, proliferation of mesenchymal cells, vascular involution and remodelling.Despite the continuous and ordered nature of the process, these findings occur in several overlapping phases, according to predominant mechanisms.

5. INFLAMMATORY PHENOMENA ASSOCIATED WITH RTGT, WITH PARTICULAR REFERENCE TO RECRUITMENT OF CELLS AND RELEASE AND MOBILIZATION OF GROWTH FACTORS

An inflammatory response, with vascular dilatation, increased vascular permeability, and diapedesis of leukocytes may precede and accompany the RTGT.Indeed, the association of several inflammatory cells of hematopoietic origin (hematopoietic stem cells) with the RTGT is a well-known fact (43-48).The cells that accumulate within the lesion compartment include neutrophils, lymphocytes, mast cells and macrophages.Between 1 and 6 h, the PMNs predominate.Thereafter, the number of monocytes/ macrophages increases, while the number of PMNs decreases dramatically.Several inflammatory mediators, such as vasoactive mediators and chemotactic factors, participate in these phenomena (49).Indeed, the signaling factors that begin the repair process, with intervention in inflammation and recruitment, migration, proliferation and differentiation of progenitor cells, include granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), stem cell factor (SCF) 06), stromal cell-derival factor-1 (SDF-1), tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), erythropoietin (EPO), interleukin-10 (IL-10) and vascular endothelial cell growth factor (VEGF).Therefore, numerous intercellular signaling pathways mediated by surface adhesion molecules and cytokines intervene in the initial phases of the RTGT.To this is added mobilization, by proteinases secreted by inflammatory cells, of factors stored in the heparin-like glycosaminoglycans of extracellular matrix, such as TGF-β, FGF2 and VEGF (50, 51).

6. STEM CELLS AND RTGT

Overlapping with the inflammatory phenomena and cell recruitment, the formation of granulation tissue is initiated, and macrophages, vascular sprouts and fibroblasts progressively appear in the interstitium and move at the same time (52) between a provisional matrix, including fibrin, fibronectin and hyaluronic acid (53-55).Thereafter, concomitant proliferation of fibroblast/myofibroblasts and capillaries originates a highly vascularized granulation tissue, in which many different types of mesodermal stem cells, including endothelial precursor cells and multipotent adult precursor cells, may participate, which may even originate other cell lineages, such as chondroblasts, osteoblasts and preadipocytes.Bearing in mind the above, recruited inflammatory cells (macrophages, mastocytes, neutrophils and eosinophils), endothelial cells and mesenchymal cells, including, among others, matrix-forming cells (fibroblasts-myofibroblasts, chondroblasts and osteoblasts), preadipocytes and precursor of arterial myointimal cells intervene in tissue undergoing repair and in maintenance of injured tissues during postnatal life.The mesenchymal cells can be tissue-derived stem cells and/or peripheral blood pluripotent stem cells (circulating progenitor cells), which form part of a system (for review, 29) comprising adult stem cells (ASC) and transit-amplifying cells (TAC), as well as the ASC niches, with their intrinsic and extrinsic regulatory mechanisms.Following, we will consider the progenitor cells related to the principal cellular components of this initial tissue: macrophages, vascular cells (endothelium and pericytes) and fibroblast-myofibroblasts.

6.1. Macrophages and progenitor cells

Macrophages that help remove damaged cellular and extracellular debris, with the capacity to release numerous cytokines (vascular endothelial growth factor, platelet derived growth factor, α and β transforming growth factors, basic and acidic fibroblast growth factors, heparin-binding epidermal growth factor) play a pivotal role in inflammation and repair (56).The origin of macrophages from bone marrow-derived peripheral blood monocytes has been accepted traditionally (57, 58).Admittedly, along with the bone marrow progenitors and blood monocytes, they form part of the mononuclear phagocyte system (59, 60).Thus, predominantly in the initial phase of RTGT, monocytes are observed adhering to the endothelium of the parent vessels (Figure 1A and 1B), as well as passing through the endothelial junctions (Figure 1C and 1D) and the pericyte-endothelial space (Figure 2A, 2B and 2C).Frequently, the monocytes/macrophages, either individually or in small clusters of two or three, simultaneously appear trapped between the EC and the pericytes, within the basal lamina (Figure 2A, 2B and 2C).Although the hematopoietic cell lineage derived from progenitor cells in the bone marrow (committed myeloid progenitor cells) is evident, several issues are currently in question, such as: a) renewal and/or local proliferation, b) functional association and interactions with other cells, c) similarities between stem cells/progenitors and macrophages, and d) contribution of other cellular components to regeneration and RTGT via transdifferentiation and/or fusion.

The replacement and renewal of macrophages principally occur from monocyte recruitment.Recently, it has been found that a significant local proliferation (59, 60) and presence of tissue proliferating monocyte-like cells (61) are also involved in the replacement and renewal of macrophages.

Association between macrophages and other cells, such as endothelial cells, pericytes and fibroblast/myofibroblasts, is morphologically evident during RTGT (Figure 2D), suggesting interactive cooperation in migration, differentiation and functional activity.

Certain similarities between stem cells/progenitors and macrophages have been pointed out.Indeed, stem and progenitor cells share some characteristics of macrophages (62).For instance, adipocyte progenitors have certain phagocytic activity, and they can phagocytize microbes and apoptotic bodies (63, 64).Likewise, preadipocytes and macrophage phenotypes are very similar, and conversion of preadipocytes to macrophages has been described (65).

Regarding their contribution of other cellular components to RTGT, certain subpopulations of monocytes /macrophages may acquire endothelial properties in angiogenic conditions (66-74), and they have been observed organizing cell columns (tunneling) in vitro (75) and in vivo (75-78), suggesting that these cords could evolve into capillary-like structures (79, 80).In this way, monocytes / macrophages may also contribute to the control and regulation of neovascularization (75), enabling the penetration of vascular progenitor cells via their tunneling activity (75, 81).Similarly, cells with both endothelial and monocyte markers have been demonstrated in tumors (82).In the inflamed cornea, CD11b+ macrophages contribute to lymphangiogenesis, originating tube-like structures that express markers of lymphatic endothelium (83).Therefore, monocyte/macrophages express greater plasticity than traditionally attributed and they may contribute to other differentiated adult lineages.Whether this plasticity of bone marrow cells occurs by transdifferentiation, fusion or functional adaptation is a controversial issue.Numerous works suggest cell fusion between bone marrow and tissue-specific cells resulting in one mechanism, which gives rise to bone marrow-derived nonhematopoietic cells (84-88), after forming polyploid cells-heterokaryons-and, subsequently, 2 euploid cells by means of cytoreductive division (87-89).On the contrary, other works propose a transdifferentiation of bone marrow cells into tissue-specific stem cells or intermediate progenitor cells (6, 90-95).Along these lines, some authors indicate the possibility that the bone marrow-derived cells improve the function of different organs (6, 90, 92, 96), expressing the specific function of the tissue of residence.Furthermore, peripheral blood mononuclear cells may contribute to granulation tissue acquiring myofibroblast-like characteristics (74, 97).The latter possibility will be addressed in other sections.

6.2. Endothelium and pericytes (preexisting microvasculature and new capillaries), ASC and TAC

Endothelium and pericytes of preexisting microvasculature have been described as progenitor cells of the granulation tissue cellular components (endothelium, new pericytes and fibroblasts/myofibroblasts).For their part, other ASC and TAC may be involved in the origin of endothelium and pericytes of new capillaries.Consequently, the endothelium and pericytes may be considered both as progenitors and/or as descendents.

6.2.1. Endothelium, ASC and TAC

6.2.1.1. Preexisting endothelium as progenitor cells

Preexisting endothelium has been considered as the principal progenitor of new endothelium in angiogenesis.The latter is the neovascularization or formation of new blood vessels from the established microcirculation by a process of sprouting from preexisting vessels.The growth factors that activate endothelial cells (EC) include vascular endothelial growth factor and basic fibroblast growth factor, produced by macrophages and fibroblasts, among others.The events classically described during capillary growth in vivo include (38): a) EC and pericyte activation; b) degradation of the basal lamina of preexisting vessels by EC (proteolytic destruction of the extracellular matrix); c) EC migration from preexisting vessels towards the angiogenic stimulus; d) EC proliferation; e) migration and proliferation of pericytes from preexisting vessels; f) formation of a new capillary vessel lumen (vascular tube formation); g) appearance of pericytes around the new capillaries; h) changes in extracellular matrix with development of a new basal lamina; i) capillary loop formation; j) early changes in the newly-formed vessels (persistence, involution and differentiation); and k) capillary network formation and eventually organization of larger microvessels.Traditionally, it has been considered that blood vessels grow by means of a movement of EC (98).This fact of EC migration is currently considered an important step during angiogenesis (99) and is directionally regulated by chemotactic, haptotactic and mechanotactic stimuli.In the initial phase of neo-vascularization, the EC degrade the vascular basement membrane of the parent vessel, protrude through its wall and begin to migrate into the interstitial space towards the angiogenic stimulus (Figure 3A).This mechanism involves macrophage angiogenic factors, which stimulate plasminogen activator and procollagenase release by the endothelial cells, with basement membrane degradation by proteases (plasmin and collagenase).Most researchers agree that these changes precede endothelial replication in such a way that migration and mitoses are independent phenomena (100-102).In other words, angiogenesis begins with pseudopodia of migrating EC (Figure 3A) and progresses to the proliferation of these cells (103-107).Therefore, angiogenic stimuli may operate through chemotaxis, and EC mitosis may be a secondary event (100, 101,108).When the entire EC migrates into the interstitium, other EC follow and loose EC sprouts or cords are formed in the perivascular stroma (Figure 3B and 3C).Mature endothelial cells, normally in a resting state, show an extremely slow turnover rate (109-112) of 2 months or more.Thus, using 3HThymidine, the labeling index is lower than 1% in normal capillary and venular EC of the retina, liver (113), myocardium, stomach (113), striated muscle (113) and skin (113-116).For example, it is 0.0.1 % in capillary EC in the adult rat retina.Since the turnover rates of EC are extremely low, angiogenesis is generally a quiescent process in the healthy adult organism (117).Nevertheless, the EC can quickly convert to a proliferative state during angiogenesis and in several related processes, such as endothelium repopulation in organ transplants, repair of large vessel defects and thrombi recanalization (115, 118).However, EC proliferation is not essential, since angiogenesis has been shown to take place even in the absence of EC replication (119).During angiogenesis, endothelial DNA synthesis occurs in parent vessels before sprouting and according to some authors as early as 6 to 8 hours after an angiogenic stimulus is applied (115).The increase of the turnover rate of EC can be considerable (Figure 3D).For example, the ³H-Thymidine labeling index of EC increases to 9% in tumors (120).The time and the exact site of EC division are controversial.For some investigators, EC mitosis appear concomitant with sprouting (119), while most authors are of the opinion that EC begin in mitosis after they start to migrate.The EC mitosis appears in both the parent vessels (Figure 3E) and the newly formed vessels.In the latter, it has been pointed out that they occur at the tip (43, 121), but it is accepted that when capillary sprout budding begins, endothelial proliferation takes place in cells following the "leader EC" (Figure 3E), but not usually at their tips.In other words, the zone of replication is closer to the parent vessel (99, 108, 122-124).The ability of angiogenic stimuli to induce replication in confluent EC is associated with disruption of cell-cell contacts (125).The replicative state and its ability to respond to endogenous mitogens may depend on cytoskeletal organization, such as microtubule destabilization or changes in the cell shape (126).Finally, the collagen in the interstitium seems to have an influence on EC proliferation (127, 128).

On the other hand, transdifferentiation of endothelial cells into smooth muscle-like cells has been suggested (129, 130).Similarly, transformation of microvascular endothelial cells into myofibroblasts has been described in different circumstances (129, 131-136).

6.2.1.2. Other endothelial cell precursors (Endothelium as descendent cells)

Postnatal neovascularization may also originate by a similar mechanism to vasculogenesis.The latter is the process by which some vessels develop in the embryo.Histogenically, vasculogenesis is defined as "in situ" capillary development from differentiating endothelial progenitor cells known as angioblasts.Until recently, blood vessel formation in postnatal life was only considered to be angiogenesis, which, though quiescent in the adult organism, may develop rapidly in several circumstances.Recently, numerous studies have contributed findings suggesting that endothelial stem cells may persist in postnatal life and may participate in neovascularization by means of a mechanism similar to vasculogenesis.In other words, the recruitment of cells during endothelialization or formation of new blood vessels in postnatal life may occur by migration of preexisting endothelial cells or by the incorporation of angioblast-like endothelial precursor cells from the circulation (Circulating angioblasts-CD-34+) (137).

Precursors of endothelial cells or endothelial progenitor cells (EPCs) have been described in bone marrow and peripheral blood (138, 139), with the possibility of homing to sites, differentiating into ECs in situ and contributing to new blood vessel formation (137, 140-145).Growth factors, such as VEGF and macrophage-colony stimulating factor, intervene in the recruitment of these cells (146, 147).In fact, multipotent adult progenitor cells cultured with VEGF differentiate into angioblasts CD34+, VE-cadherin+ and Flk1+ cells and subsequently into cells that express endothelial markers and that have in vitro functional characteristics indistinguishable from those of mature endothelial cells, able to form tubes and express markers of endothelial cells (148).Likewise, these cells can contribute to neoangiogenesis in vivo during RTGT and tumorigenesis (146, 148, 149).Thus, a higher population of endothelial precursor cells is associated with inflammatory breast tumors (150).Therefore, endothelial progenitor cells may contribute to support the integrity of the vascular endothelium by means of neoangiogenesis and rejuvenation of the endothelial monolayer (137, 151, 152).For instance, undifferentiated progenitor cells may participate in vascular remodeling from the recipient to the graft in heart transplants (153-155), although this concept is currently a matter of intense debate, since there are discrepancies in the rates of chimerism in damaged vessels and hearts (153, 154, 156-159).Indeed, some authors indicate that the majority of the cells in the vessel wall are recipient-derived after aortic allografts (154, 160-162), cardiac transplantation (155, 160) or vein grafting (163).On the contrary, other authors have described minimal contribution from recipient cells.Thus, endothelial repopulation by bone marrow-derived recipient cells is found to be an early event in transplanted allograft hearts, which decreases in frequency over time (164).

Two types of endothelial progenitor cells in the peripheral blood have recently been described: the early EPCs (137, 165-167) or monocyte-derived circulating angiogenic cells (71, 168), and the late EPCs (166, 167, 169) or outgrowth endothelial cells (OECs) (165, 170).The early EPCs are a heterogenous population, show early growth, express CD34, CD31, Flk-1, Tie-2, Ve-cadherin, KDR, CD14, CD105, vWF, CD45, CD11c, CD163, VEGFR-2 (71, 137, 165, 171, 172) and are incapable of tube formation (137, 165).They produce VEGF, IL-8, HGF, G-CSF (137, 173) and low level nitric oxide, and have a good angiogenic potential (137), although proliferative capacity is limited (173).The late EPCs or OECs are a homogenous population (137), show late outgrowth (137, 165, 170), express Flk-1, vWF, CD36, Ve-Cadherin, CD31, VEGFR-2, Tie-2 (165, 170), and are capable of tube formation (137, 165).They have low level cytokine secretion (137) and high level nitric oxide production (137, 165), and also have a good angiogenic potential (137) with highly proliferative capacity (143).The early EPCs predominantly originate from CD14+ precursors, while the OECs come from a CD14- population of cells (165).Recently, it has been pointed out that the level of circulating CD34+KDR+ endothelial progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes (174).Likewise, there may be a higher presence of restenosis when the circulating endothelial progenitor cells decrease (175).Furthermore, the numbers of circulating CD34+ and CD133+KDR+ endothelial progenitor cells increase after acute myocardial infarction (176), and there is impaired function of progenitor cells in patients with congestive heart failure (177).Mobilized peripheral blood mononuclear cells (easily non invasively obtained from the peripheral blood, with CD-34+ cells increased, and rich in angiogenic factors and cytokines), obtained from peripheral blood mononuclear cells after granulocyte colony stimulating factor intervention, have been effective in clinical application for severe arteriosclerosis obliterans of lower extremities and for severe diabetic foot ischemia (178-180).

6.2.2. Pericytes, ASC and TAC

6.2.2.1.Preexisting pericytes as precursor cells

In addition to participating in the maintenance of blood vessel wall integrity, perivascular cells (pericytes, adventitial or Rouget cells, pericyte-like cells) (181, 182) retain considerable mesenchymal potentiality and may have the capacity to differentiate into other cell types (183-190), such as fibroblasts (47, 191), chondroblasts (192), osteoblasts (193-196), preadipocytes (191, 197), vascular smooth muscle cells and myointimal cells (198, 199).In the initial phases of RTGT, the pericytic microvasculature undergoes a sudden, brief and intense pericyte proliferation (37).In this way, autoradiographic studies show an increased amount of label in pericytes of postcapillary venules and capillaries (Figure 3D) (37, 101, 114, 115, 200, 201).Besides, sequential morphologic findings in the pericytes during the initial phase of granulation tissue formation agree with the hypothesis that pericytes may be an important source of new fibroblasts (129, 183).These sequential morphologic findings include: a) the pericytes, bulging from preexisting vessels, shorten their processes and increase their somatic volume (Figure 2B and 2C and 4B); b) the nuclei contain prominent nucleoli and their cytoplasms show numerous ribosomes, either singly or in aggregates (Figure 2B and 2C); c) multiple profiles of rough endoplasmic reticulum are observed (Figure 2B and 2C); d) the pericyte basal lamina is frequently disrupted and fragmented; and e) numerous pericytes project into the extravascular space, appear detached from the vessel walls and adopt transitional cell forms between themselves and fibroblast-like cells (Figure 2D) (37).As mentioned above, the migrating monocytes contribute to the detachment and mobilization of the activated pericytes in the pre-existing pericytic microvasculature (Figure 2A, 2B and 2C).

Using Monastral Blue as a tracer for labeling cells in the walls of pericytic microvasculature, the marker was first observed in pericytes (Figure 4A) and subsequently in pericytes bulging from preexisting vessels (Figure 4B, 4C and 4D), and in fibroblast-myofibroblasts (Figure 4E and F) during granulation tissue formation (37), as well as in chondroblasts (202) (Figure 4G), osteoblasts (Figure 4H) (195) and myointimal cells after specific induction (203, 204).

Moreover, cells specifically expressing known markers of pericytes also express markers characteristic of stem cell population (205).Endosialin, which may be a marker of mesenchymal stem cells, has been identified in activated myofibroblasts and pericytes (206, 207).Mesenchymal stem cell populations have been described residing in the microvasculature of the tissue origin (perivascular niche) (29, 37, 183, 189, 192, 199, 208-211).Thus, the majority of dental pulp stem cells express pericyte associated antigen (208) and co-express Notch 3 (regulating stem cell fate specification) and RgsT (marker for pericytes) (209), suggesting a perivascular niche of postnatal mesenchymal stem cells.Likewise, a population of multipotent CD34-positive, adipose stromal cells shares pericyte (chondroitin sulfate proteoglycan, CD140a and CD140b) and mesenchymal (CD10; CD13 and CD90) surface markers (212).Although the mechanisms controlling pericyte differentiation are poorly defined, Wnt/beta-catenin signaling stimulates chondrogenic and inhibits adipogenic differentiation of the pericytes (213).

In soft tissue lesions, some authors consider pericytes as the progenitor cells of several pseudosarcomatous processes (214, 215), malignant fibrous histiocytoma (216) and mixoid liposarcoma (217).Pericytes and endothelial precursor cells are also important participants among the many cells that give rise to progressing malignant disease (218).

6.2.2.2. Other pericyte precursors (pericytes as descendent cells)

Recruitment of pericytes to newly formed vessels from fibroblast and bone marrow progenitor cells has been described (these progenitors will be considered in sections 6.3.1. and 6.3.2.Here we present the controversy about the participation of the bone marrow in pericyte and endothelial cell origin).

Although bone marrow progenitor cells can be recruited during the formation of new vessels and vasculature, remodelling (219-221), there is controversy about their participation in pericyte and endothelial cell origin.As mentioned above, using neovascularization models, several authors point out those BM-derived precursors give rise to endothelial cells (146, 150, 222-224); while others have proposed that bone marrow, precursor cells only develop pericytes but not endothelial cells (219-221).Recently, it has been indicated (221) that new corneal vessels have a dual source: bone marrow-derived precursor cells (53% of all neovascular pericytes) and pre-existing limbal capillaries (47% of all neovascular pericytes).Of the bone marrow-derived pericytes, 96% expressed CD45 and 92% CD11b, which suggested their hematopoietic origin.Using mouse chimera in brain repair after ischemia (225), two populations of bone marrow-derived cells were observed: one in the brain parenchyma (predominantly microglia) and another associated with remodeling blood vessels in perivascular location.The latter were negative for endothelial cell markers, but expressed desmin and were immunoreactive for angiogenic factors, endothelial growth factor and transforming growth factor beta, suggesting pericytes.Mobilization and recruitment of bone marrow-derived pericyte progenitor cells have also been described in tumors (219, 226, 227).Evidence that mature vessels develop from pericyte/macrophages networks and that almost all macrophages and more than half of the pericytes derived from the bone marrow have been shown using subcutaneous matrigel plugs (81).By contrast, only 10% of endothelial cells exhibit a bone marrow origin (81).

Pericyte progenitor cells have been described from non-endothelial mesenchymal cells isolated from the rat aorta.The latter, cultured in a serum-free medium with fibroblast growth factor, proliferated slowly and formed spheroidal colonies, expressing CD34, Tie-2, NG2, nestin and PDGF α and β receptors.When cocultured in collagen with isolated endothelial cells, they transformed into pericytes (228).

6.3. Fibroblast/myofibroblasts, ASC and TAC

The origin of the heterogeneous population of fibroblast/myofibroblasts, which respond to mediators of inflammation and intervene in the integrity of the tissues, and in the production (matrix-synthesizing cells), deposition and degradation (matrix-degrading cells) of extracellular matrix proteins, in contraction (myofibroblasts) to reduce the size of the wound, in growth

factor secretion and in the proliferation and differentiation of other cells (229-232), may be from tissue-derived stem cells and/or peripheral blood pluripotent stem cells (circulating progenitor cells).Among the principal putative progenitor tissue cells are the fibroblasts themselves and the pericytes.According to the outline of this work, below we will consider the fibroblasts as precursor or descendent cells.

6.3.1. Preexisting fibroblasts as precursor cells

A conventional hypothesis is that local relatively quiescent fibroblasts around the injured tissue migrate, proliferate and originate the new activated fibroblasts and myofibroblasts, with extracellular matrix protein production and wound contraction (233-235).Therefore, fibroblasts, normally involved in their quiescent state in slow turnover of the extracellular matrix (primary producers of type I, III and V collagen and fibronectin, contributors of the basement membrane by secretion of laminine and type IV collagen, and with remodelling capacity by means of fibroblast-derived matrix metalloproteinases) undergo a change in phenotype to a proliferative, synthetic (Figure 5A) and contractile state (myofibroblasts) (Figure 5B) (236).Indeed, in the margin of lesions, the resting fibroblasts proliferate, express integrin receptors (that bind fibronectin and fibrin on fibroblasts - 55, 237), migrate (by means of an active fibroblast-derived proteolytic system, including collagenases, gelatinase A, plasminogen activator and stromelysin - 238, 239) and differentiate into myofibroblasts, with extracellular matrix protein production (240, 241), secretion of growth factors and chemotactic factors, migration, contraction (production of alpha smooth muscle actin) (235) and parenchyma interactions (dynamic cross-talk between fibroblasts and parenchyma cells).The myofibroblasts temporarily acquire their expression of α-smooth muscle actin, which disappears progressively (between 15 and 30 days).It is generally accepted that collagen deposition continues long after myofibroblasts decline.Therefore, myofibroblasts are temporarily activated before collagen producing fibroblasts (232).Growth factors, such as transforming growth factor β1 (242) and platelet derived growth factor (243), contribute to activate the local fibroblasts.In this way, other cells may influence their proliferation, differentiation, extracellular matrix synthesis and survival.For instance, adipose-derived stem cells have the capacity to promote human dermal fibroblast migration, proliferation, and secretion by cell-to-cell direct contact and by paracrine activation through secretory factors, such as PDGF, insulin-like growth factor, bFGF, TGF-β, HGF and VEGF (244).As mentioned above, endosialin, a marker of mesenchymal stem cells, is expressed by myofibroblasts and pericytes (206).

Induced pluripotent stem cells (IP cells) can be generated from adult human fibroblasts (245).Indeed, cells similar to human embryonic stem cells in morphology, proliferation, surface markers, gene expression, promoter activities, in vitro differentiation, telomerase activity and teratoma formation were generated from adult human fibroblasts by retrovirus-mediated transfection of four transcription factors: Oct3/4, Sox2, c-Myc and Klf4 (245).Therefore, IPS cells can be derived from somatic cells and may thus lead to important drug discoveries and advances in regenerative medicine (246).

6.3.2. Other fibroblasts/myofibroblasts precursors (fibroblasts/myofibroblasts as descendent cells)

Although RTGT fibroblast/myofibroblasts originally derive from resident tissue fibroblasts in the proximity of the RTGT (55, 237), this possibility does not preclude that pericyte, bone marrow derived cells or other transdifferentiated cells contribute to their heterogenous fibroblast/myofibroblast population (247).The origin from pericytes has been previously considered (section 6.2.2.1.).The bone marrow precursors, bone marrow mesenchymal cells and fibrocytes, will be discussed below.

Since 1970, fibroblast colony formation from monolayer cultures of bone marrow and blood cells (fibroblast colony-forming units) has been demonstrated (248-251), evidencing a bone marrow origin for fibroblasts.A rare cell within human bone marrow mesenchymal stem cell culture (multipotent adult progenitor cells or MAPCs) has been identified (148, 251-253) and immature mesenchymal cells derived from the bone marrow appear to be constantly repopulating normal and injured connective tissues (254-255).In general, bone marrow mesenchymal AS cells are located in the complex system of the bone marrow stroma (bone marrow stromal cells), and they can be isolated by means of Stro-1+ antibody recognition (256, 257).These cells have the capacity to differentiate into mesenchymal lineage cells and, with appropriate environmental conditions into cells of different embryonic origin, such as cells with visceral mesoderm, neuroectoderm and endoderm characteristics.In other words, these cells have high capacity of transdifferentiation and plasticity (20, 258-260).Indeed, the bone marrow mesenchymal cells may differentiate phenotypically into adipose, cartilage, bone, vascular smooth muscle, skeletal and cardiac muscle, hepatocytes, neural elements and hematopoietic-supportive stromal cells (6, 9, 15, 17, 147, 260-268).Epidermal growth factor is considered as a candidate for ex vivo expansion of bone marrow-derived mesenchymal ASC (269).Transcription factors, which regulate the expression of the differentiation genes of the aforementioned cells, participate in this differentiation process.For example, C/EBP and PPARγ families and other transcription factors intervene in adipocyte (270, 271) and Cbfa1/Runx2 in osteocyte (272, 273) differentiation.Besides, there are regulation control mechanisms such as hormones and growth factors.Using bone marrow mesenchymal ASC, alveolar bone cells and periosteal cells for tissue-engineered bone formation, it has been demonstrated that the periosteal cells originate approximately double the amount of newly formed bone than bone marrow mesenchymal cells (274).Other sections of this work describe the role of transplanted bone marrow cells in organ and solid tissue regeneration.

A bone marrow-derived circulating population of mesenchymal progenitors, termed "fibrocytes" (275-279) or "fibrocyte precursors", which rapidly enter sites of tissue injury, was identified a decade ago (275).Subsequent studies have demonstrated that these cells express markers of leukocytes (CD45, LSP1), monocyte lineage (CD11a, CD11b, CD13, CD32, CD64), as well as hematopoietic stem cell/progenitor antigens (CD34, CD105) and fibroblast products (collagen I and III, fibronectin, vimentin MMP9) (275-288).Adherent cultured fibrocytes develop a spindle-shaped morphology (275) and express MHC, class II and co-stimulatory molecules (CD80 and CD 86).Recently, it has been pointed out that CD34+ fibrocytes, which are present in the connective tissue of virtually all human organs, derive from circulating CD14+ monocytes (289).These cells secrete numerous cytokines and have the property of expressing smooth muscle actin, while retaining CD34 expression, when they acquire myofibroblast-like differentiation (277).These cells have the ability to present antigen in vitro and in vivo (276, 280, 290), and cultured fibrocytes in vitro and in vivo facilitate angiogenesis by means of proteolysis of the basal lamina (secretion of active matrix metalloproteinase 9-MMP-9) and by secretion of growth factors, such as VEGF, β FGF and PDGF (291).As we shall see below, fibrocytes intervene in development of fibrotic lesions, connective tissue disease, atherosclerosis and in tumor stroma formation.On the other hand, the use of marrow-derived stem cells as a therapeutic procedure has been considered, for instance, to accelerate healing in chronic ulcers (292).

An immunosuppressive effect on adult dendritic cells differentiated from CD 34+ hemopoietic progenitor cells has been contributed, suggesting that mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway (293).

Another postulated origin is that epithelial cells undergo epithelial to mesenchymal transdifferentiation (see below).

7. INVOLUTIVE PHENOMENA.RTGT AS A "PARACRINE TRANSITIONAL ORGAN"

Several components of the granulation tissue undergo involution, which is highly evident in the newly formed vessels.Indeed, angiogenesis ceases and most of the endothelial cells disintegrate drastically because of apoptosis, only persisting the preferential vasculature.In this mechanism intervene antiangiogenesis factors (angioprotein, angiostatin and endostatin) (294) and thrombospondins 1 and 2, among other matrix molecules (295).At first, the numerous disintegrating vessels show marked intravascular accumulation of factor-releasing platelets (platelet thrombus) (Figure 6A, 6B, 6C, 6D and 6E), and the granulation tissue becomes a "paracrine transitional organ".Subsequently, homogenized platelets, endothelial cell debris and basal membrane residues are observed (Figure 6F, 6G and 6H).The fibroblasts acquire myofibroblast phenotype, with cytoplasmic actin-containing filaments and cell-matrix and cell-cell linkages (296), intervening in tissue contraction, collagen synthesis and catabolism of collagen in combination with matrix metalloproteinases and inhibitors of metalloproteinases (297).

8. RTGT AND CELLULAR DIFFERENTIATION, DEDIFFERENTIATION, TRANSDIFFERENTIATION AND FUSION

As mentioned above, the putative cells with the capacity to originate myofibroblasts during RTGT, such as fibroblasts, pericytes and marrow stromal cells, can give rise to other cell lineages and differentiate "in vitro" and "in vivo" into osteoblasts (Figure 4H), chondroblasts (Figure 4G), preadipocytes (Figure 7), or smooth muscle cells by means of growth factors and specialized induction (183, 195, 202, 204, 298-307).This generalized system may complete the repair from locally resident mesenchymal cells that provide tissue-specific progeny, such as adipose, muscle, periostium, trabecular bone, synovium and dermis-derived mesenchymal cells (195, 303).Furthermore, these mesenchymal cells are highly plastic and they may also produce progeny of endodermal and ectodermal lines (20, 258, 271, 308, 309).Cell contacts with neighbouring cells and cell environment interactions intervene in the cellular differentiation (see above).On the other hand, differentiation may not entirely be a unidirectional process during RTGT and dedifferentiation leads to the reversion towards a more immature phenotype.For instance, by means of reversine, myotubes may undergo dedifferentiation back into progenitor cells, which may originate osteoblasts or adipocytes (310).Likewise, without reverting to a more primitive phenotype, mesenchymal stem cells may be capable of transdifferentiating into various phenotypes including astrocytes and neurons (12, 16, 311-315).Finally, cell fusion may occur, although it seems to be biologically irrelevant for its extreme rarity (316), except for macrophages, which are able to fuse among themselves and with other cell types (317).

9. ASC, RTGT AND TISSUE ENGINEERING

Future directions of research in tissue engineering include the development of multi-tissue organs, imitating what occurs during embryonic development and in adult-life repair processes.Indeed, in embryonic development, a bidirectional molecular dialog between parenchymal cells and stromal cells is necessary for normal organ development and function (318-321).In adult life, the repair process reproduces these interactions between regenerative elements (parenchyma) and RTGT components (stroma).In this way, RTGT lend the regenerative parenchyma morphofunctional support and facilitate a multistep mechanism, involving angiogenesis and organization by recruitment of fibroblast-myofibroblasts and by producing and remodeling extracellular matrix components.For instance, in skin wounds, fibrin clot forms a provisional scaffold for cell migration, proliferation and differentiation.In tissue engineering, parenchyma-stroma interactions similar to RTGT appear to be essential and they may play an active and instructive role in programming the final tissue structure and function.In other words, it is necessary to develop prototype tissue engineered matrices to support the simultaneous growth of different cell types (322) and a rapid induction of angiogenesis (322-327).The strategies in tissue engineering may utilize: a) cell suspensions or cell-sheets, b) biomolecules, c) matrices in combination with cells and/or biomolecules, and d) 3-D environments or scaffolds with seeding and culturing specific cell types (328).The scaffolds for tissue engineering should have several properties, such as degradability, biocompatibility, non-immunogenicity, easy reproduction and the possibility to incorporate and deliver bioactive molecules (growth factors, peptides, lyophilized cell fractions, etc.).Among these conditions are the mechanical properties, since stiff or soft scaffolds may be used.For instance, the latter are more suitable for adipose tissue engineering (329, 330).In addition, in these strategies, it is fundamental to promote regeneration and repair.Indeed, optimum procedures, combining scaffolds, cells and/or biomolecules, should be capable of inducing adhesion, migration, proliferation, differentiation, angiogenesis and production of new extracellular matrix, in a manner similar to that which occurs during regeneration and RTGT, in which the process results in the formation of new structures that reproduce the original morphology and function.

10. ASC AND RTGT IN PATHOLOGY

10.1. ASC, Organization, abnormal RTGT and Fibrosis

Examples of organization are the creation of new masses of fibrous tissue in blood clots or inflammatory exudates with fibrin deposits through granulation tissue (331).Thus, organization of thrombus initiates with leukocyte and macrophage infiltration (inflammatory stage), followed by neovascularization, and fibroblast/myofibroblast proliferation (proliferative stage) and progressive collagen deposition and contraction, while myofibroblasts decline (contraction stage) (332).To this can be added microvascular involution, persistence of preferential vessels and recanalization.Monocytes/macrophages play a central role in thrombus organization (333).For example, the gene for a chemokine link to macrophage activation CXCL14 is upregulated (332).

Abnormal RTGT may occur by defect or excess.An example of deficient RTGT are diabetic ulcers, in which ASC descendents are modified in their proliferation, differentiation and functional activity, with impaired neovascularization, increasing levels of proteinases and decreasing synthesis of collagen.Several factors are involved in these modifications, such as vascular disease with subsequent ischemia (anoxia and reducing nutrients), impaired granulocytic chemotaxis and function with infections and prolonged inflammation, associated neuropathy and defective macrophage function (334, 335).

Examples of excessive RTGT are hypertrophic scars and keloids with higher collagen production in which several factors intervene, such as increased and exaggerated responses to fibrogenic cytokines (enhanced expression of TGF-β, mRNA (336), mutations in regulatory genes and abnormal epidermal mesenchymal interactions - 337, 338-).Fibrocytes also contribute to the fibroblast population in these lesions (281, 339).

Examples of fibrotic lesions are idiopathic pulmonary fibrosis and systemic fibroses in which an important contribution of bone marrow-derived cells in the early stages has been pointed out (276, 287, 288, 340-343).Evasion of myofibroblasts from immune surveillance has been proposed as a mechanism for tissue fibrosis.Indeed, this mechanism may occur since myofibroblasts possess Fas/Fasl-pathway-dependent characteristics that allow them to escape from immune surveillance and resulting organ fibrosis (345).Recently, transformation of microvascular endothelial cells into myofibroblasts has been considered as having a potential role in the etiology and pathology of fibrotic disease (136, 346).

10.2. ASC, RTGT and atherosclerosis

In atherosclerosis, as in RTGT, inflammatory phenomena precede and accompany the process, quiescent cells are induced to proliferate rapidly, new blood vessels are formed, stromal cells migrate, the extracellular matrix is invaded, the new tissue is remodeled and the same factors initiate and regulate the process.In this way, the cellular events in the formation of atherosclerotic lesions after injury include regeneration of endothelial monolayer, infiltration of monocyte cells and myointimal cell proliferation (347).The regeneration of the endothelial monolayer may have the same sources as those previously described for neovascularization, namely, by migrating and proliferating preexisting neighbouring endothelial cells or by circulating progenitor endothelial cells (bone marrow-derived cells expressing CD133 or CD34 - 137, 139, 142-)(see above).

The traditional hypothesis is that myointimal cells in atherosclerotic lesions are derived from the medial smooth muscle cells (348-351), which migrate from the media into the intima, acquiring a synthetic phenotype with matrix synthesis.This hypothesis is now shrouded in doubt and the myointimal cell origin remains the subject of ongoing debate, since myointimal cells may be considered from a variety of sources (352).Indeed, the following possibilities may be considered: arterial media layer origin (SMCs and SMC related cells), adventitial progenitor cells and bone-marrow-derived circulating cells.

The hypothesis of arterial media layer SMC origin (348, 349, 351, 353-365) is based on the following: a) the cells present in the intimal thickening (myointimal cells - neointimal SMC cells) correspond in appearance to smooth muscle cells (348, 354, 355, 357-360, 362-364, 366), b) these myointimal cells show the same early enzymatic reaction as cells of the innermost third part of the media layer (356, 361), c) muscle cells from the media layer have been observed crossing the "gaps" of the internal elastic lamina, suggesting a capacity to move through this membrane (354, 357, 363, 366), and d) tritiated thymidine incorporates in the internal zone of the media layer, prior to appearing in the intimal layer (353, 367).Nevertheless, differences between media and neointimal SMC cytoskeletal features, growth pattern, responses to growth factors /cytokines and matrix synthesis/degradation have been described (368).An origin of myointimal cell from a preexisting and distinct subpopulation of the media layer SMC has also been pointed out (369).

The hypothesis of adventitial progenitor cells (199, 203, 204, 370-376) is based on the following: a) In autoradiographic studies on the incorporation of ³H-thymidine, during intimal thickening developing in occluded arterial segments, DNA synthesis was first seen in the adventitia, fundamentally in the vasa-vasorum pericytes, later in the adjacent media and subsequently in the intimal thickening (Figure 8A, 8B and 8D) (199), with contribution of myofibroblasts to neointimal formation (377).Coronary adventitial fibroblasts display proliferation, collagen synthesis and phenotypic heterogeneity in response to stimulation, whereas medial SMCs maintain a highly differentiated phenotype (371).Abundant progenitor cells expressing stem cell markers (Sca-1; C-kit; CD-34 and FlK-1) are present in the adventitia (372, 374) and can differentiate into myofibroblasts, migrate to arterial media or intima layers and differentiate into SMCs (372, 374, 376).Sca-1+ cells obtained from explanted cultures of adventitial tissues and transferred to the adventitial side of vein grafts were found in atherosclerotic lesions of the intima (372).The adventitia may contribute progenitor cells from the interstitium (fibroblasts) or from the vasa-vasorum.When human vascular adventitial fibroblasts were cultured in appropriate media, they showed myogenic differentiation, with increased expression of smooth muscle actin and calponin (378).Regarding vasa-vasorum, microvessel penetration into the arterial wall from the adventitial layer has been observed in atherosclerosis, not only in its later stages, but also in the earliest stages of its precursor lesions, such as intimal thickening (Figure 8C, 8E, 8F, 8G, 8H, 8I and 8J) (41, 199).This initial response may be considered as a particular form of granulation tissue formation and is followed by a rapid microvascular involution.In this way, it has been postulated that arterial intimal thickening results from a similar mechanism to that of the organization of thrombus, with subsequent events depending on whether or not the arterial circulation has been interrupted.On interruption, there is both a penetration of the vasa-vasorum and a myointimal differentiation from the adventitial recruited cells (pericytes, fibroblasts or circulating progenitor cells), whereas when the arterial circulation has remained unchanged there is no vasa-vasorum penetration and the intimal thickening originates from recruited cells migrating from the arterial vasa-vasorum and adventitia (199, 204).Using a technique that specifically labels venules, predominantly postcapillary venules, in addition to recruited macrophages, newly formed endothelial cells and a supplementary population of fibroblast- myofibroblasts and myointimal cells were contributed from the periarterial microvascularization during arterial intimal thickening formation (204).The fibroblasts and the vasa-vasorum pericytes are the principal candidates in adventitial participation in the arterial myointimal cells (199, 372, 374, 376).The aberrant differentiation of pericytes may contribute to the development and progression of atherosclerosis and calcific vasculopathies (213).

The hypothesis of bone-marrow-derived circulating cells is based on the presence of marrow stromal cells as stem cells for non-hematopoietic tissues (379) and on the discovery of circulating fibrocytes as collagen-producing cells of the peripheral blood (287, 380), which appear in the fibrous cup and in lipid-rich areas of human and experimentally-induced atherosclerotic plaques (381-384).Indeed, bone marrow provides inflammatory cells (lymphocytes and monocytes that become foam cells) and myofibroblast/myointimal cells, whose balance affects plaque stability (385, 386).These precursor cells have been considered in other sections of this paper.In this order, bone-marrow-derived mesenchymal cells can serve as a new cell source of smooth muscle cells in vessel engineering (387).Likewise, repopulation of endothelium and medial smooth muscle cells from both circulating and adjacent ends of non-affected artery cells has been demonstrated in rat patent arterial segments devoid of mural cells (adventitial, smooth muscle and endothelial cells) by local application of glycerol (Figure 9A) (42).The morphologic events in the early stages of cellular recruitment is reminiscent of those occurring in granulation tissue, with the following steps: a) reendothelialization (Figure 9A), apparently from adjacent ends of non-affected artery; b) presence of monocytes between endothelium and internal elastic lamina (Figure 9B); c) migration towards the media layer of monocytes and endothelial cells, crossing the elastic internal lamina fenestrations (Figure 9C); d) formation of vascular channels with endothelial and mural cells in the innermost area of the media layer with continuity between arterial lumen endothelial cells and those in tunnelized structures (Figure 9D); e) involution of the newly-formed vascular channels, presenting platelets and red cells in their lumens (Figure 9E) and, simultaneously, proliferation of spindle cells, which finally repopulate the arterial media layer acquiring smooth muscle cell phenotype (Figure 9F).

10.3. ASC, RTGT and tumor stroma

The tumor stroma is a major factor influencing the growth and progression of cancer (388), including survival, migration, proliferation, invasion and metastasis.This tissue microenvironment is a complex and dynamic structure with similar characteristics, biological markers and components to RTGT, as well as with the same origin.These similarities also include induction of angiogenesis and stromal acquisition of the myofibroblast phenotype.Indeed, as occurs with RTGT, the tumor stroma population of cells consists of vascular elements (endothelium and pericytes), fibroblast-myofibroblasts and macrophages, with variable association of other inflammatory cells, arranged in a modified extracellular matrix (388-395).

As with RTGT, in tumor stroma growth intervene interactions between parenchymal (tumoral) cells and activated stromal cells, as well as several cellular and extracellular matrix molecules.Unlike normal connective tissue, which behaves as an antiprogressive environment of the neoplasia, the tumor stroma after tumor-like genetic lesions (396-398) acquires an active role in cancer progression with paracrine-acting factors.Thus, the tumor stroma provides physical architecture and blood supply (oxygen and nutrients), removes metabolic and biological waste and contributes growth factors, cytokines and extracellular matrix proteins, including adhesion proteins and proteases (394, 399-403).For instance, macrophages, fibroblasts and endothelial cells express and secrete metalloproteinases (404), which hydrolyze collagen, laminin, fibronectin and vitronectin (402, 405).Actively recruited tumor-associated macrophages release V-G factor stimulators of angiogenesis (VEGF, HGF, MMP2, IL-8) as well as hypoxia-induced transcription factors.An enhancing role of tumor-associated myofibroblasts, facilitating the invasiveness of colon tumors, has been demonstrated by means of co-injection of activated fibroblasts and tumor cells (406).The difference between tumor fibroblast-myofibroblasts and activated fibroblasts in RTGT is that tumor fibroblast-myofibroblasts change their phenotype and do not undergo apoptosis and elimination, remaining perpetually activated.The origin of tumor fibroblasts may be tissue-resident pericytes and fibroblasts (407), bone marrow-derived mesenchymal cells (394, 408-411), fibrocytes (289, 410) or parenchymal and local cancer cell transdifferentiation (412).Endosialin, a marker of mesenchymal stem cells, is expressed by tumor-associated myofibroblasts and pericytes (206, 207) (See above).CD34+ fibrocytes, which act as antigen presenting cells during carcinoma invasion, lose CD34 positivity expression for a gain of alpha-SMA expression (myofibroblast characteristic), contributing to the stroma tumor and to tumor escape from host immune control (289).Mesenchymal stem cells from post-natal bone marrow are considered as an emerging tool for cell-mediated gene therapy in several pathologic processes, including cancer therapy.Indeed, the homing of mesenchymal cells is favored in sites of active tumorigenesis, and these cells may be used as cell carriers for delivering anticancer factors (cytokines, interferons, replicable adenovirus, pro-drugs, among others) (413).

12. OVERVIEW AND CLINICAL PROMISE

The extensive cellular plasticity of the principal cellular components in RTGT (local and circulating bone marrow derived progenitor cells), supported by so many different lines of evidence (Table 1), is reasonably based, but relatively recent and some of the different capabilities of being precursor or descendent cells are not very defined.Therefore, further research is needed to confirm which of these proposed precursor cells are genuine pluripotential stem cells or which are only capable of expressing different properties and functional roles.

In all likelihood, these precursor cells reside in virtually all postnatal tissues and organs (414) and, in our opinion, the perivascular niche, with pericyte-like cells, including pericytes, homing cells from the bone marrow (fibrocytes and MSC) and perivascular fibroblasts, is the most solid hypothesis, now emerging (29, 37, 183-205, 208-215, 370, 415-421).In this hypothesis (Figure 10), the perivascular region (with pericyte-like cells) is the niche of progenitor cells and the substrate of regulatory mechanisms.Indeed, pericyte-like cells, originate new-pericytes, fibroblast-myofibroblasts (and related cells) and some subsets of macrophages.The regulatory mechanisms include: a) regulation of quiescent and angiogenic stages of blood vessels (cell-cell contacts and soluble factors produced by pericytes and EC), b) mesenchymal cell proliferation and differentiation control, and c) interactions between transmigrating cells (e.g.monocytes) and perivascular niche resident cells.

This hypothesis is difficult to confirm owing to the following: a) the heterogenous cellular population in a perivascular location with like-morphology (416); b) the need to identify the descendent cells in a location far from the niche (415, 422); c) the cells in the putative niche express several molecular markers, none of which is general or specific; and d) the markers are not continually expressed in the pericytic niche and descendent cells.This variable expression depends on species, location, diverse characteristics, functional state (422), distinct overlapping populations, and the quiescent or angiogenic stage of blood vessels (423).There is even controversy among laboratories.Other procedures may be required in addition to the morphology, gene expression and phenotypic criteria for specific location of MSC niches.In this way, we have selectively labeled cells in the wall of the pericytic microvasculature of adipose tissue (a putative vascular niche of MSC), using an exogenous marker, which has been subsequently observed in culture cells of adherent MSC obtained from this tissue (nonpublished observations).

The mesenchymal stem cells isolated from various tissues and involved in RTGT (with innate ability to home to sites of tissue repair) are a therapeutic promise, which will increase when their lineage, full functional differentiation capacity and requirements for favoring cell renewal over differentiation during expansio in cultures is better understand (paradox between "in vitro" promise and "in vivo" efficacy -424).Clinical applications could involve the following (394, 395, 424): 1) to engineer different tissues both "ex vivo" and "in vivo", such us cartilage (e.g.joint, nose, ear and trachea), bone (e.g.craneofacial and long bone defects) and myocardium (acute myocardial infarction), 2) to produce growth factors (e.g.member of the BMP family), proteins (e.g.protein deficiency disorders-hemophilias), collagen and trophic factors, 3) to induce angiogenesis and inhibit apoptosis, 4) to form "guiding strands" to promote direct growth of new axons during central nervous system or spinal cord injury, 5) to provide stromal support for transplanted cells (e.g.bone marrow transplants), and 6) to modify the tumor associated stroma and/or use as delivery vehicles for anti-cancer therapies.In this way, the future strategies include (394, 395): a) modification of the genetically altered tumor stroma mesenchymal stem and descendent cells (unlike homeostatic RTGT cells, they might initiate and/or enhance tumor growth); b) use of mesenchymal stem cells as cellular delivery vehicles of antitumor agents (specific tropism of mesenchymal stem cells that survive and proliferate inside the tumor and that may act as a "mini pump", e.g., active and passive immunotherapy, therapeutic gene products, interferon β (394) (See above); c) actions to alter the expression of some cell surface receptors and to inhibit tumor promoting interactions, targeting one or multiple molecules (growth factors, growth factor receptors, adhesion molecules and enzymes - e.g., recombinant humanized anti-VEGF mab Bevacizumab and anti-CD105 antibody-); d) modulation of the tumor microenvironment by eliminating the stromal cells; and e) interference with the remodelling of the extracellular matrix (e.g.inhibitors of proteases - MMPS-).

11.REFERENCES

1 S. H. Orkin: Stem cell alchemy. Nat Med 6, 1212-1213 (2000)
doi:10.1038/81303
2 H. M. Blau, T. R. Brazeltonand and J.M. Weimann: The evolving concept of a stem cell: entity or function? Cell 105, 829-841 (2001)
doi:10.1016/S0092-8674(01)00409-3
3 D. S. Krause, N. D. Theise, M. I. Collector, O. Henegariu, S. Hwang, R. Gardner, S. Neutzel and S. J. Sharkis: Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369-377 (2001)
doi:10.1016/S0092-8674(01)00328-2
4 J. J. Minguell, A. Erices and P. Conget: Mesenchymal stem cells. Exp Biol Med 226, 507-520 (2001)

5 S.I. Morrison: Stem cell potential: can anything make anything? Curr Biol 11, R7-9 (2001)
doi:10.1016/S0960-9822(00)00033-6
6 G. Ferrari, G. Cusella-De Angelis, M. Coletta, E. Paolucci, A. Stornaiuoio, G. Cossu and F. Mavilio: Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528-1530 (1998)
doi:10.1126/science.279.5356.1528
7 C. R. Bjornson, R. L. Rietze, B. A. Reynolds, M. C. Magli and A. L. Vescovi: Turning brain into blood: a hematopoietic late adopted by adult neural stem cells in vivo. Science 283, 534-537 (1999)
doi:10.1126/science.283.5401.534
8 K. A. Jackson and M. A. Goodell: Hematopoietic potential of stem cells isoiated from murine skeletal muscle. Proc Natl Acad Sci USA 96, 14482-14486 (1999)
doi:10.1073/pnas.96.25.14482
9 G. C. Kopen, D. J. Prockop and D. G. Phinney: Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96, 10711-10716 (1999)
doi:10.1073/pnas.96.19.10711
10 B. E. Petersen, W. C. Bowen, J. S. Greenberger and J. P. Goff: Bone marrow as a potential source of hepatic oval cells. Science 284, 287-298 (1999a)
doi:10.1126/science.284.5417.1168
11 B. E. Petersen, W C. Bowen, K. D. Patrene, W. M. Mars, A. K. Sullivan, N. Murase and S. S. Boggs: Bone marrow as a potential source of hepatic oval cells. Science 284, 1168-1170 (1999b)
doi:10.1126/science.284.5417.1168
12 T. R. Brazelton, F. M. Rossi, G. I. Keshet and H. M. Blau: From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775-1779 (2000)
doi:10.1126/science.290.5497.1775
13 D. L. Clarke, C. B. Johansson, J. Wilbertz, B. Veress, E. Nilsson, H. Karlstrom, U. Lendahl and J. Frisen: Generalized potential of adult neural stem cells. Science 288, 1660-1663 (2000)
doi:10.1126/science.288.5471.1660
14 R. Galli, U. Borello, A. Gritti, M. G. Minasi, C. Bjornson, M. Coletta, M. Mora, M. G. De Angelis, R. Fiocco, G. Cossu and A.L. Vescovi: Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci 3, 986-991 (2000)
doi:10.1038/79924
15 E. Lagasse, H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I.L. Weissman and M. Grompe: Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6, 1229-1234 (2000)
doi:10.1038/81326

16 E. Mezey and K. J. Chandross: Bone marrow: a possible alternative source of cells in the adult nervous system. Eur J Pharmacol 405, 297-302 (2000)
doi:10.1016/S0014-2999(00)00561-6
17 D. Orlic, J. Kajstura, S. Chimenti, I. Jakoniuk, S. M. Anderson, B. Li, J. Pickel, R. McKay, B. Nadal-Ginard, D. M. Bodine, A. Leri and P. Anversa: Bone marrow cells regenerate infarcted myocardium. Nature 410, 701-705 (2001)
doi:10.1038/35070587
18 M. Korbling, R. L. Katz, A. Khanna, A. C. Ruifrok, G. Rondon, M. Albitar, R. E. Champlin and Z. Estrov: Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 346, 738-746 (2002)
doi:10.1056/NEJMoa3461002
19 E.V. Badiavas, M. Abedi, J. Butmarc, V. Falanga and P. Quesenberry: Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol 196, 245-250 (2003)
doi:10.1002/jcp.10260
20 Y. Jiang, B. N. Jahagirdar, R. L. Reinhardt, R. E. Schwartz, C. D. Keene, X. R. Ortiz-Gonzalez, M. Reyes, T. Lenvik, T. Lund, M. Blackstad, J. Du, S. Aldrich, A. Lisberg, W. C. Low, D.A. Largaespada and C.M. Verfaillie: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41-49 (2002a)
doi:10.1038/nature00870
21 A. J. Wagers and I. L. Weissman: Plasticity of adult stem cells. Cell 116, 639-648 (2004)
doi:10.1016/S0092-8674(04)00208-9
22 G. D. Richardson, E. C. Arnott, C. J. Whitehouse, C. M. Lawrence, A. J. Reynolds, N. Hole and C. A. Johada: Plasticity of rodent and human hair follicle dermal cells: Implications for cell therapy and tissue engineering. J Invest Dermatol SP 10, 180-183 (2005)
doi:10.1111/j.1087-0024.2005.10101.x
23 Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007 (2007)
doi:10.1038/nature06196
24 R. Schofield: The relationship between the spleen colony-forming cell and the haemopoietic stem cell: a hypothesis. Blood Cells 4, 7-25 (1978)

25 F. M. Watt and B. L. M. Hogan: Out of Eden: stem cells and their niches. Science 287, 1427-1430 (2000)
doi:10.1126/science.287.5457.1427
26 A. Spradling, D. Drummond-Barbosa and T. Kai: Stem cells find their niche. Nature 414, 98-104 (2001)
doi:10.1038/35102160
27 E. Fuchs, T. Tumbar and G. Guasch: Socializing with their neighbors: stem cells and their niche. Cell 116, 769-778 (2004)
doi:10.1016/S0092-8674(04)00255-7
28 B. Ohlstein, T. Kai, E. Decotto and A. Spradling: The stem cell niche: themes and variations. Curr Opin Cell Biol 16, 693-699 (2004)
doi:10.1016/j.ceb.2004.09.003

29 L. Díaz-Flores Jr, J. F. Madrid, R. Gutiérrez, H. Varela, F. Valladares, H. Alvarez-Argüelles and L. Díaz-Flores: Adult stem and transit-amplifying cell location. Histol Histopathol 21, 995-1027 (2006)

30 J. D. Cashman, A. C. Eaves and C. J. Eaves: Granulocyte-macrophage colony-stimulating factor modulation of the inhibitory effect of transforming growth factor-beta on normal and leukemic human hematopoietic progenitor cells. Leukemia 6, 886-892 (1992)

31 D.K. Podolsky: Regulation of intestinal epithelial proliferation: a few answers, many questions. Am J Physiol 264, G179-86 (1993)

32 K. K. Johe, T. G. Hazel, T. Muller, M. M. Dugich-Djordjevic and R.D. McKay: Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10, 3129-3140 (1996)
doi:10.1101/gad.10.24.3129
33 N. Fortunel, J. Hatzfeld, S. Kisselev, M. N. Monier, K. Ducos, A. Cardoso, P. Batard and A. Hatzfeld: Release from quiescence of primitive human hematopoietic stem/progenitor cells by blocking their cell-surface TGF-beta type II receptor in a short-term in vitro assay Stem Cells 18, 102-111 (2000)
doi:10.1634/stemcells.18-2-102
34 D. L. Crowe, B. Parsa and U. K. Sinha: Relationships between stem cells and cancer stem cells. Histol Histopathol 19, 505-509 (2004)

35 S. N. Salm, P. E. Burger, S. Coetzee, K. Goto, D. Moscatelli and E. L. Wilson: TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts. J Cell Biol 170, 81-90 (2005)
doi:10.1083/jcb.200412015
36 C. Niemann: Controlling the stem cell niche: right time, right place, right strength. Bioessays 28, 1-5 (2006)
doi:10.1002/bies.20352
37 L. Díaz-Flores, R. Gutiérrez and H Varela: Behavior of postcapillary venule pericytes during postnatal angiogenesis. J Morphol 213, 33-45 (1992)
doi:10.1002/jmor.1052130105
38 L. Díaz-Flores, R. Gutiérrez and H. Varela: Angiogenesis: an update. Histol Histopathol 9: 807-843 (1994a)

39 L. Díaz-Flores, R. Gutiérrez, F. Valladares, H. Varela and M. Pérez: Intense vascular sprouting from rat femoral vein induced by prostaglandins E1 and E2. Anat Rec 238, 68-76 (1994b)
doi:10.1002/ar.1092380109
40 L. Díaz-Flores, R. Gutiérrez and H. Varela: Induction of neovascularization in vivo by glycerol. Experientia 52, 25-30 (1996)
doi:10.1007/BF01922411
41 J. F. Madrid, L. Diaz-Flores, R. Gutierrez, H. Varela, F. Valladares, N. Rancel and F. Rodriguez: Participation of angiogenesis from rat femoral veins in the neovascularization of adjacent occluded arteries. Histol Histopathol 13, 1-11 (1998)

42 L. Díaz-Flores, J. F. Madrid, R. Gutiérrez, F. Valladares, M. Díaz, H. Varela and L. Díaz-Flores Jr.: Arterial wall neovascularization induced by glycerol. Histol. Histopathol 16, 1175-1181 (2001)

43 E. R. Clark and E. L. Clark: Microscopic observations on the growth of blood capillaries in the living mammal. Am J Anat 64, 251-301 (1939)
doi:10.1002/aja.1000640203
44 R. A. Mc Donald: Origin of fibroblasts in experimental healing wounds: autoradiographic studies using tritiated thymidine. Surgery 46, 376-382 (1959)

45 H. C. Grillo: Origin of fibroblasts in wound healing. An autoradiographic study of inhibition of cellular proliferation by local x-irradiation. Ann Surg 157, 453-467 (1963)

46 M. A. Jennings and H. W. Florey: Healing. In: General pathology. 4th ed. H. W. Florey (ed). Lloyd-Luke (Medical Books) Ltd., W. B. Saunders Co. Philadelphia. pp 480-548 (1970)

47 R. Ross, N. B. Everett and R. Tyler: Wound healing and collagen formation. VI. The origin of the wound fibroblast studied in parabiosis. J. Cell Biol 44, 645-654 (1970)
doi:10.1083/jcb.44.3.645
48 G. B. Ryan and W.G. Spector: Macrophages turnover in inflamed connective tissue. Proc R Soc Lond (Biol) 174, 269-292 (1970)

49 R. A. F. Clark: The molecular and cellular biology of wound repair. 2nd ed. Plenum Press. New York (1996)

50 P. Mignatti and D.B. Rifkin: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161-195 (1993)

51 K. Stellos, H. Langer, K. Daub, T. Schoenberger, A. Gauss, T. Geisler, B. Bigalke, I. Mueller, M. Schumm, I. Schaefer, P. Seizer, B. F. Kraemer, D Siegel-Axel, A. E. May, S. Lindemann and M. Gawaz: Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 117, 206-215 (2008)
doi:10.1161/CIRCULATIONAHA.107.714691
52 T. K. Hunt, ed. Wound healing and wound infection: theory and surgical practice. Appleton-Century-Crofts. New York (1980)

53 R. A. F. Clark, J. M. Lanigan, P. DellaPelle, E. Manseau, H. F. Dvorak and R. B. Colvin: Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 79, 264-269 (1982)
doi:10.1111/1523-1747.ep12500075
54 B. P. Toole: Proteoglycans and hyaluronan in morphogenesis and differentiation. In: E. D. Hay, ed. Cell biology of extracellular matrix. 2nd ed. Plenum Press.: 305-341. New York (1991)

55 S. A. McClain, M. Simon, E. Jones, A. Nandi; J. O. Gailit; M. G. Tonnesen; D. Newman and R. A. F. Clark: Mesenchymal cell activation is the rate-limiting step of granulation tissue induction. Am J Pathol 149, 1257-1270 (1996)

56 A. J. Singer and R. A. Clark: Cutaneous wound healing. N Engl J Med 341, 738-746 (1999)
doi:10.1056/NEJM199909023411006
57 P. Martin: Wound healing - aiming for perfect skin regeneration. Science 276, 75-81 (1997)
doi:10.1126/science.276.5309.75
58 S. Gordon: Development and distribution of mononuclear phagocytes: relevance to inflammation. J. I. Gallin and R. Synderman eds. Inflammation: Basic Principles and Clinical Correlates, 35-48 Lippincott, Williams and Wilkins Philadelphia, PA (1999)

59 D. A. Hume, I. L. Ross, S. R. Himes, R. T. Sasmono, C. A. Wells and T. Ravasi: The mononuclear phagocyte system revisited. J Leukoc Biol 72, 621-627 (2002)

60 D. A. Hume. The mononuclear phagocyte system. Cur Op Immunol 18, 49-53 (2006)
doi:10.1016/j.coi.2005.11.008
61 C. J. Pascual, P. R. Sanberg, W. Chamizo, S. Haraguchi, D. Lerner, M. Baldwin and N. S. El-Badri: Ovarian monocyte progenitor cells: phenotypic and functional characterization. Stem Cells Dev 14, 173-180 (2005)
doi:10.1089/scd.2005.14.173
62 G. M. Charrière, B. Cousin, E. Arnaud, C. Saillan-Barreau, M. André, A. Massoudi, C. Dani, L. Pénicaud and L. Casteilla: Macrophage characteristics of stem cells revealed by transcriptome profiling. Exp Cell Res 312, 3205-3214 (2006)
doi:10.1016/j.yexcr.2006.06.034
63 B. Cousin, O. Munoz, M. Andre, A. M. Fontanilles, C. Dani, J. L. Cousin, P. Laharrague, L. Casteilla and L. Penicaud: A role for preadipocytes as macrophage-like cells. FASEB J 13, 305-312 (1999)

64 C. Saillan-Barreau, B. Cousin, M. Andre, P. Villena, L. Casteilla and L. Penicaud: Human adipose cells as candidates in defense and tissue remodeling phenomena. Biochem Biophys Res Commun 309, 502-505 (2003)
doi:10.1016/j.bbrc.2003.08.034
65 G. Charrière, B. Cousin, E. Arnaud, M. André, F. Bacou, L. Penicaud and L.Casteilla: Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem 278, 9850-9855 (2003)
doi:10.1074/jbc.M210811200

66 B. Fernandez Pujol, F. C. Lucibello, U. M. Gehling, K. Lindemann, N. Weidner, M. L. Zuzarte, J. Adamkiewicz, H. P. Elsasser, R. Muller and K. Havemann: Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 65, 287-300 (2000)
doi:10.1046/j.1432-0436.2000.6550287.x
67 Z. Gao, V. C. McAlister and G. M. Williams: Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 357, 932-933 (2001)
doi:10.1016/S0140-6736(00)04217-3
68 A. Schmeisser, C. D. Garlichs, H. Zhang, S. Eskafi, C. Graffy, J. Ludwig, R. H. Strasser and W. G. Daniel: Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 49, 671-680 (2001)
doi:10.1016/S0008-6363(00)00270-4
69 K. Havemann, B. F. Pujol and J. Adamkiewicz: In vitro transformation of monocytes and dendritic cells into endothelial like cells. Adv Exp Med Biol 522. 47-57 (2003)

70 W. D. Ito and E. Khmelevski: Tissue macrophages: "satellite cells" for growing collateral vessels? A hypothesis. Endothelium 10, 233-235 (2003)
doi:10.1080/713715240
71 J. Rehman, J. Li, C. M. Orschell and K. L. March: Peripheral blood "endotelial progenitor cells" are derived from monocytes/macrophages and secrete angiogenic growth factors. Circulation 107, 1164-1169 (2003)
doi:10.1161/01.CIR.0000058702.69484.A0
72 C. Urbich, C. Heeschen, A. Aicher, E. Dernbach, A. M. Zeiher and S. Dimmeler: Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation 108, 2511-2516 (2003)
doi:10.1161/01.CIR.0000096483.29777.50
73 G. Nowak, A. Karrar, C. Holmen, S. Nava, M. Uzunel, K. Hultenby and S. Sumitran-Holgersson: Expression of vascular endothelial growth factor receptor-2 or Tie-2 on peripheral blood cells defines functionally competent cell populations capable of reendothelialization. Circulation 110, 3699-3707 (2004)
doi:10.1161/01.CIR.0000143626.16576.51
74 A. Jabs, G. A. Moncada, C. E. Nichols, E. K. Waller and J. N. Wilcox: Peripheral blood mononuclear cells acquire myofibroblast characteristics in granulation tissue. J Vasc Res 42, 174-180 (2005)
doi:10.1159/000084406
75 M. Anghelina, P. Krishnan, L. Moldovan and N. I. Moldovan: Monocytes/macrophages cooperate with progenitor cells during neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles. Am J Pathol 168, 529-541 (2006)
doi:10.2353/ajpath.2006.050255
76 N. I. Moldovan, P. J. Goldschmidt-Clermont, J. Parker-Thornburg, S. D. Shapiro, P. E. Kolattukudy: Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ Res 87, 378-384 (2000)

77 M. Anghelina, A. Schmeisser, P. Krishnan, L. Moldovan, R. H. Strasser and N. I. Moldovan: Migration of monocytes/macrophages in vitro and in vivo is accompanied by MMP12-dependent tunnel formation and by neovascularization. Cold Spring Harb Symp. Quant Biol 67, 209-215 (2002)
doi:10.1101/sqb.2002.67.209
78 M. Anghelina, P. Krishnan, L. Moldovan and N. I. Moldovan: Monocytes and macrophages form branched cell columns in matrigel: implications for a role in neovascularization. Stem Cells Dev 13, 665-676 (2004)
doi:10.1089/scd.2004.13.665
79 N. I. Moldovan: Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel's end. J Hematother Stem Cell Res 11, 179-94 (2002)
doi:10.1089/152581602753658394
80 N. I. Moldovan and T. Asahara: Role of blood mononuclear cells in recanalization and vascularization of thrombi: past, present, and future. Trends Cardiovasc Med 13, 265-269 (2003)
doi:10.1016/S1050-1738(03)00108-7
81 U. Tigges, E. G. Hyer, J. Scharf and W. B. Stallcup: FGF2-dependent neovascularization of subcutaneous Matrigel plugs is initiated by bone marrow-derived pericytes and macrophages. Development 135, 523-532 (2008)
doi:10.1242/dev.002071
82 J. R. Conejo-Garcia, R. J. Buckanovich, F. Benencia, M. C. Courreges, S. C. Rubin, R. G. Carroll and G. Coukos: Vascular leukocytes contribute to tumor vascularization. Blood 105, 679-681 (2005)
doi:10.1182/blood-2004-05-1906
83 K. Maruyama, M. Ii, C. Cursiefen, D. G. Jackson, H. Keino, M. Tomita, N. Van Rooijen, H. Takenaka, P. A. D'Amore, J. Stein-Streilein, D. W. Losordo and J. W. Streilein: Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115, 2363-2372 (2005)
doi:10.1172/JCI23874
84 N. Terada, T. Hamazaki, M. Oka, M. Hoki, D. M. Mastalerz, Y. Nakano, E. M. Meyer, L. Morel, B. E. Petersen and E. W. Scott: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542-545 (2002)
doi:10.1038/nature730
85 Q. L. Ying, J. Nichols, E. P. Evans and A. G. Smith: Changing potency by spontaneous fusion. Nature 416, 545-548 (2002)
doi:10.1038/nature729
86 M. Alvarez-Dolado, R. Pardal, J. M. Garcia-Verdugo, I. R. Fike, H. O. Lee, K. Pfefter, C. Lois, S. I. Morrison and A. Alvarez-Buylla: Fusion of bonemarrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425, 968-973 (2003)
doi:10.1038/nature02069
87 G. Vassilopoulos, P. R. Wang and D. W. Russell: Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901-904 (2003)
doi:10.1038/nature01539
88 X. Wang, H. Willenbring, Y. Akkari, Y. Torimaru, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold, S. Olson and M. Grompe: Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897-901 (2003)
doi:10.1038/nature01531
89J. M. Weimann, C. B. Johansson, A. Trejo and H. M. Blau: Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transpiant. Nat Cell Biol 5, 959-966 (2003)
doi:10.1038/ncb1053
90 M. A. LaBarge and H. M. Blau: Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589-601 (2002)
doi:10.1016/S0092-8674(02)01078-4
91 A. Deb, S. Wang, K. A. Skelding, D. Miller, D. Simper and N. M. Caplice: Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 107, 1247-1249 (2003)
doi:10.1161/01.CIR.0000061910.39145.F0
92 A. Ianus, G.C. Holz, N. D. Theise, M. A. Hussain: In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111, 843-850 (2003)
doi:10.1172/JCI200316502, doi:10.1172/JCI16502
93 S. D. Tran, S. R. Pillemer, A. Dutra, A. J. Barrett, M. I. Brownstein, S. Key, E. Pak, R. A. Leakan, A. Kingman, K. M. Yamada, B. J. Baum and E. Mezey. Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study. Lancet 361, 1084-1088 (2003)
doi:10.1016/S0140-6736(03)12894-2
94 R. G. Harris, E. L. Herzog, E. M. Bruscia, J. E. Grove, J. S. Van Arnam and D. S. Krause: Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305, 90-93 (2004)
doi:10.1126/science.1098925
95 Y. Y. Jang, M. I. Collector, S. B. Baylin, A. M. Diehl and S. I. Sharkis. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 6, 532-539 (2004)
doi:10.1038/ncb1132
96 M. Yamada, H. Kubo, S. Kobayashi, K. Ishizawa, M. Numasaki, S. Ueda, T. Suzuki and H. Sasaki: Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol 172, 1266-1272 (2004)

97 L. Díaz-Flores, J. G. López, A.R. Lucas, G. Sánchez y H. Varela: Transformación de histiocitos en fibroblastos facultativos. Demostración ultraestructural. Morf Norm Patol (A) 3, 527-538 (1979)

98 W. His: Untersuchungen über die erste Anlage des Wirbelthierleibes. F. C. W. Vogel. Leipzig. (1868)

99 D. H. Ausprunk and J. Folkman: Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14, 53-65 (1977)
doi:10.1016/0026-2862(77)90141-8
100 M. M. Sholley, M. A. Gimbrone and R. S. Cotran: Cellular migration and replication in endothelial regeneration: a study using irradiated endothelial cultures. Lab Invest 36, 18-25 (1977a)

101 M. M. Sholley, T. Cavallo and R. S. Cotran: Endothelial cell proliferation in inflammation. I. Autoradiographic studies following thermal injured to the skin of normal rats. Am J Pathol 89, 277-296 (1977b)

102 R. T. Wall, L. A. Harker and G. E. Striker: Humar endothelial migration and stimulation by a released platelet factor. Lab Invest 39, 523-529 (1978)

103 K. Matsuhashi: Electron microscopic observation of the corneal vascularization. (Report I). J Clin Ophthalmol 14, 121-127 (1961)

104 K. Matsuhashi: Experimental study on the corneal vascularization. II. Electron microscope observation on the corneal vascularization. Nippon Ganka Gakkai Zasshi 66, 939-952 (1962)

105 S. Sugiura and H. Matsuda: Electron microscopic studies on corneal neo-vascularization. Nippon Ganka Gakkai Zasshi 73, 1208-1221 (1969)

106 I. Yamagami: Electronmicroscopic study on the cornea. I. The mechanism of experimental new vessel formation. Jpn J Ophthalmol 14, 41-58 (1970)

107 J. S. Mc Cracken, P. C. Burger and G. K. Klintworth: Morphologic observations on experimental corneal vascularization in the rat. Lab Invest 41, 519-530 (1979)

108 J. Folkman: Angiogenesis: initiation and control. Ann NY Acad Sci 401, 212-227 (1982)
doi:10.1111/j.1749-6632.1982.tb25720.x
109 G. H. Algire, H. W. Chalkley, F. Y. Legallais and H. D. Park: Vascular reactions of normal and malignant tumors in vivo: I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6, 46-73 (1945)

110 R. Altschul: Endothelium. Its Development, morphology, function and pathology. MacMillan Co. New York. pp 28-31 (1954)

111 S. C. Sparagen, V. P. Bond and L. K. Dahl: Role of hyperplasia in vascular lesions of cholesterol-fed rabbits studied with thymidine-H3 autoradiography. Circ Res 11, 329-336 (1962)

112 J. Folkman and R. Cotran: Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol 16, 207-248 (1976)

113 I. F. Tannock and S. Hayashi: The proliferation of capillary endothelial cells. Cancer Res 32, 77-82 (1972)

114 T. Cavallo, R. Sade, J. Folkman and R. S. Cotran: Tumor angiogenesis. Rapid induction of endothelial mitoses demonstrated by auto radiography. J Cell Biol 54, 408-420 (1972)
doi:10.1083/jcb.54.2.408
115 T. Cavallo, R. Sade, J. Folkman and R. S. Cotran: Ultrastructural autoradiographic studies of the early vasoproliferative response in tumor angiogenesis. Am J Pathol 70, 345-362 (1973)

116 P. J. Polverini, R. S. Cotran and M. M. Sholley: Endothelial proliferation in the delayed hypersensitivity reaction: an autoradiographic study. J Immunol 118, 529-537 (1977)

117 D. Shweiki, A. Itin, G. Neufeld, H. Gitay-Goren and E. Keshet: Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 91, 2235-2243 (1993)
doi:10.1172/JCI116450
118 J. Folkman: What is the role of endothelial cells in angiogenesis. Lab Invest 51, 601-602 (1984)

119 M. M. Sholley, G. P. Ferguson, H. R. Seibel, J. L. Montuor and J. D. Wilson: Mechanisms of neovascularization. Vascular sprouting can occur without proliferation of endothelial cells. Lab Invest 51, 624-634 (1984)

120 J. Denekamp and B. Hobson: Endothelial cell proliferation in experimental tumors. Br J Cancer 46, 711-720 (1982)

121 G. Hadfield: Granulation tissue. Ann Roy Coll Surg Eng 9, 397-407 (1951)

122 W. J. Cliff: Kinetics of wound healing in rabbit ear chambers: time lapse cinemicroscopic study. Q J Exp Physiol 50, 79-89 (1965)

123 R. A. F. Clark: Cutaneous tissue repair: Basic biologic considerations. I. J Am Acad Dermatol 13, 701-725 (1985)

124 J. Folkman: How is blood vessel growth regulated in normal and neoplastic tissue. Cancer Res 46, 467-473 (1986)

125 L. M. Bavisotto, S. M. Schwartz and R. L. Heimark: Modulation of Ca-dependent intercellular adhesion in bovine aortic and human umbilical vein endothelial cells by heparin-binding growth factors. J Cell Physiol 143, 39-51 (1990)
doi:10.1002/jcp.1041430106
126 L. Liaw and S. M. Schwartz: Microtubule disruption stimulates DNA synthesis in bovine endothelial cells and potentiates cellular response to basic fibroblast growth factor. Am J Pathol 143, 937-948 (1993)

127 J. A. Madri and K.S. Stenn: Aortic endothelial cell migration. I. Matrix requirements and composition. Am J Pathol 106, 180-186 (1982)

128 A. M. Schor, S. L. Schor and T. D. Allen: Effects of culture conditions on the proliferation morphology and migration of bovine aortic endothelial cells. J Cell Sci 62, 267-285 (1983)

129 H. Varela, L. Díaz-Flores, J. Linares, G. Sánchez and T. Caballero: Transformación de las células endoteliales y pericitos en miofibroblastos. Estudio ultraestructural. Morf Norm Patol (A) 2, 215 - 231 (1978)

130 M. G. Frid, V. A. Kale, K. R and Stenmark: Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 90, 1189-1196 (2002)
doi:10.1161/01.RES.0000021432.70309.28
131 L. I. Romero, D. N. Zhang, G. S. Herron and M. A. Karasek: Interleukin-1 induces major phenotypic changes in human skin microvascular endothelial cells. J Cell Physiol 173, 84-92 (1997)
doi:10.1002/(SICI)1097-4652(199710)173:1<84::AID-JCP10>3.0.CO;2-N
132 M. M. Kennedy, J. J. O'Leary, J. L. Oates, S. B. Lucas, D. D. Howells, S. Picton and J. O. McGee: Human herpes virus 8 (HHV-8) in Kaposi's sarcoma: lack of association with Bcl-2 and p53 protein expression. Mol Pathol 51, 155-159 (1998)

133 A. V. Moses, K. N. Fish, R. Ruhl, P. P. Smith, J. G. Strussenberg, L. Zhu, B. Chandran and J. A. Nelson: Long-term infection and transformation of dermal microvascular endothelial cells by human herpesvirus 8. J Virol 73, 6892-6902 (1999)

134 V. Chaudhuri and M. Karasek: Mechanisms of microvascular wound repair. II. Injury induces transformation of endothelial cells into myofibroblasts and the synthesis of matrix proteins. In Vitro Cell Dev Biol Anim 42, 314-319 (2006)

135 M. Gröger, H. Niederleithner, D. Kerjaschki and P Petzelbauer: A previously unknown dermal blood vessel phenotype in skin inflammation. J Invest Dermatol 127, 2893-2900 (2007)
doi:10.1038/sj.jid.5701031
136 M. A. Karasek: Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease? Med Hypotheses 68, 650-655 (2007)
doi:10.1016/j.mehy.2006.07.053
137 T. Asahara, T. Murohara, A. Sullivan, M. Silver, R. van der Zee, T. Li, B. Witzenbichler, G. Schatteman and J. M. Isner: Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964-977 (1997)
doi:10.1126/science.275.5302.964
138 S. Watt, S. Gschmeissner and P. Bates: PECAM-1: its expression and function as a cell adhesion molecule on hemopoietic and endothelial cells. Leuk Lymphoma 17, 229-235 (1995)
doi:10.3109/10428199509056827
139 M. Peichev, A. J. Naiyer, D. Pereira, Z. Zhu, W. J. Lane, M. Williams, M. C. Oz, D. J. Hicklin, L. Witte, M. A. S. Moore and S. Rafii: Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95, 952-958 (2000)

140 S. Rafii, F. Shapiro, J. Rimarachin, R. L. Nachman, B. Ferris, B. Weksler, M. A. Moore and A. S. Asch: Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood 84, 10-18 (1994)

141 S. I. Nishikawa, S. Nishikawa, M. Hirashima, N. Matsuyoshi and H. Kodama: Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 125, 1747-1757 (1998)

142 U. M. Gehling, S. Ergun, U. Schumacher, C. Wagener, K. Pantel, M. Otte, G. Schuch, P. Schafhausen, T. Mende, N. Kilic, K. Kluge, B. Schafer, D. K. Hossfeld and W. Fiedler: In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 95, 3106-3112 (2000)

143 Y. Lin, D. J. Weisdorf, A. Solovey and R. P. Hebbel: Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 105, 71-77 (2000).
doi:10.1172/JCI8071
144 N. Quirici, D. Soligo, L. Caneva, F. Servida, P. Bossolasco and G. L. Deliliers: Differentiation and expansion of endothelial cells from human bone marrow CD133+ cells. Br J Haematol 115, 186-194 (2001)
doi:10.1046/j.1365-2141.2001.03077.x
145 R.G. Bagley, J. Walter-Yohrling, X. Cao, W. Weber, B. Simons, B. P. Cook, S. D. Chartrand, C. Wang, S. L. Madden and B. A. Teicher: Endothelial precursor cells as a model of tumor endothelium: characterization and comparison with mature endothelial cells. Cancer Res 63, 5866-5873 (2003)

146 T. Asahara, H. Masuda, T. Takahashi, C. Kalka, C. Pastore, M. Silver, M. Kearne, M. Magner and J. M. Isner: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85, 221-228 (1999)

147 T. Takahashi, C. Kalka, H. Masuda, D. Chen, M. Silver, M. Kearney, M. Magner, J. M. Isner and T. Asahara: Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5, 434-438 (1999)
doi:10.1038/8462, doi:10.1038/7434
148 M. Reyes, A. Dudek, B. Jahagirdar, L. Koodie, P. H. Marker and C. M. Verfaillie: Origin of endothelial progenitors in human postnatal bone marrow J Clin Invest 109, 337-346 (2002)
doi:10.1172/JCI200214327, doi:10.1172/JCI14327
149 E. S. de Bont, J. E. Guikema, F. Scherpen, T. Meeuwsen, W. A. Kamps, E. Vellenga and N. A. Bos: Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. Cancer Res 61, 7654-7659 (2001)

150 K. Shirakawa, M. Shibuya, Y. Heike, S. Takashima, I. Watanabe, F. Konishi, F. Kasumi, C. K. Goldman, K. A. Thomas, A. Bett, M. Terada and H. Wakasugi: Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer. Int J Cancer 99, 344-351 (2002)
doi:10.1002/ijc.10336
151 N. Werner, S. Junk, U. Laufs, A. Link, K. Walenta, M. Bohm and G. Nickenig: Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res 93, e17-e24 (2003)
doi:10.1161/01.RES.0000083812.30141.74
152 D. Kong, L. G. Melo, M. Gnecchi, L. Zhang, G. Mostoslavsky, C. C. Liew, R. E. Pratt and V. J. Dzau: Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 110, 2039-2046 (2004)
doi:10.1161/01.CIR.0000143161.01901.BD
153 A. Saiura, M. Sata, Y. Hirata, R. Nagai and M. Makuuchi: Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med 7, 382-383 (2001)
doi:10.1038/86394
154 K. Shimizu, S. Sugiyama, M. Aikawa, Y. Fukumoto, E. Rabkin, P. Libby and R. N. Mitchell: Host bone-marrow cells are a source of donor intimal smooth-muscle-like cells in murine aortic transplant arteriopathy. Nat Med 7, 738-741 (2001)
doi:10.1038/89121
155 M. Sata, A. Saiura, A. Kunisato, A. Tojo, S. Okada, T. Tokuhisa, H. Hirai, M. Makuuchi, Y. Hirata and R. Nagai: Hematopoietic stem cells differentiate into vascular cells that particípate in the pathogenesis of atherosclerosis. Nat Med 8, 403-409 (2002)
doi:10.1038/nm0402-403
156 M. A. Goodell, K. Brose, G. Paradis, A. S. Conner and R. C. Mulligan: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183, 1797-1806 (1996)
doi:10.1084/jem.183.4.1797
157 K. A. Jackson, S. M. Majka, H. Wang, J. Pocius, C. J. Hartley, M. W. Majesky, M. L. Entman, L. H. Michael, K. K. Hirschi and M. A. Goodell: Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107, 1395-1402 (2001)
doi:10.1172/JCI12150
158 F. Quaini, K. Urbanek, A. P. Beltrami, N. Finato, C. A. Beltrami, B. Nadal-Ginard, J. Kajstura, A. Leri and P. Anversa: Chimerism of the transplantad heart. N Engl J Med 346, 5-15 (2002)
doi:10.1056/NEJMoa012081
159 S. Y. Corbel, A. Lee, L. Yi, J. Duenas, T. R. Brazelton, H. M. Blau and F. M. Rossi: Contribution of hematopoietic stem cells to skeletal muscle. Nat Med 9, 1528-1532 (2003)
doi:10.1038/nm959
160 J. L. Hillebrands, F. A. Klatter, B. M. van den Hurk, E. R. Popa, P. Nieuwenhuis and J. Rozing: Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest 107, 1411-1422 (2001)
doi:10.1172/JCI10233
161 Y. Hu, F. Davison, B. Ludewig, M. Erdel, M. Mayr, M. Url, H. Dietrich and Q. Xu: Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation 106, 1834-1839 (2002a)
doi:10.1161/01.CIR.0000031333.86845.DD
162 Y. Hu, F. Davison, Z. Zhang and Q. Xu: Endothelial replacement and angiogenesis in arteriosclerotic lesions of allografts are contributed by circulating progenitor cells. Circulation 108, 3122-3127 (2003)
doi:10.1161/01.CIR.0000105722.96112.67
163 Y. Hu, M. Mayr, B. Metzler, M. Erdel, F. Davison and Q. Xu: Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res 91, e13-20 (2002b)
doi:10.1161/01.RES.0000037090.34760.EE
164 Rezai, S. Y. Corbel, D. Dabiri, A. Kerjner, F. M. Rossi, B. M. McManus and T. J. Podor: Bone marrow-derived recipient cells in murine transplanted hearts: potential roles and the effect of immunosuppression. Lab Invest 85, 982-991 (2005)
doi:10.1038/labinvest.3700302
165. Gulati, D. Jevremovic, T. E. Peterson, S. Chatterjee, V. Shah, R. G. Vile and R. D. Simari: Diverse origin and function of cells with endothelial phenotype obtained from adult human blood. Circ Res 93, 1023-1025 (2003)
doi:10.1161/01.RES.0000105569.77539.21
166. Hur, C. H. Yoon, H. S. Kim, J. H. Choi, H. J. Kang, K. K. Hwang., B. H. Oh, M. M. Lee and Y. B. Park: Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler. Thromb Vasc Biol 24, 288-293 (2004)
doi:10.1161/01.ATV.0000114236.77009.06
167. H. Yoon, J. Hur, K. W. Park, J. H. Kim, C. S. Lee, I. Y. Oh, T. Y. Kim, H. J. Cho, H. J. Kang, I. H. Chae, H. K. Yang, B. H. Oh, Y. B. Park and H. S. Kim: Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 112, 1522-1524 (2005)
doi:10.1161/CIRCULATIONAHA.104.503433
168. Rehman, J. Li, L. Parvathaneni, G. Karlsson, V. R. Panchal, C. J. Temm, J. Mahenthiran and K. L. March: Exercise acutely increases circulating endothelial progenitor cells and monocytes-/macrophage-derived angiogenic cells. J Am Coll Cardiol 43, 2314-2318 (2004)
doi:10.1016/j.jacc.2004.02.049
169 Q.Shi, S. Rafii, M. H. Wu, E. S. Wijelath, C. Yu, A. Ishida, Y. Fujita, S. Kothari, R. Mohle, L. R. Sauvage, M. A. Moore, R. F. Storb and W.P. Hammond: Evidence for circulating bone marrow-derived endothelial cells. Blood 92, 362-367 (1998)

170 . A. Ingram, L. E Mead, D. B. Moore, W. Woodard, A. Fenoglio, M. C. Yoder: Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105, 2783-2786 (2005)
doi:10.1182/blood-2004-08-3057
171 C. Kalka, H. Masuda, T. Takahashi, W. M. Kalka-Moll, M. Silver, M. Kearney, T. Li, J. M. Isner and T. Asahara: Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 97, 3422-3427 (2000)
doi:10.1073/pnas.070046397
172 B. Assmus, V. Schachinger, C. Teupe, M. Britten, R. Lehmann, N. Dobert, F. Grunwald, A. Aicher, C. Urbich, H. Martin, D. Hoelzer, S. Dimmeler and A. M. Zeiher: Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106, 3009-3017 (2002)
doi:10.1161/01.CIR.0000043246.74879.CD
173 S. Murasawa, J. Llevadot, M. Silver, J. M. Isner, D. W. Losordo and T. Asahara: Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation 106, 1133-1139 (2002)
doi:10.1161/01.CIR.0000027584.85865.B4
174 N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm and G. Nickenig: Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353, 999-1007 (2005)
doi:10.1056/NEJMoa043814
175 J. George, I. Herz, E. Goldstein, S. Abashidze, V. Deutch, A. Finkelstein, Y. Michowitz, H. Miller and G. Keren: Number and adhesive properties ofcirculating endothelial progenitor cells in patients with in-stent restenosis. Arterioscler Thromb Vasc Bio 23, e57-e60 (2003)
doi:10.1161/01.ATV.0000107029.65274.db
176 S. Shintani, T. Murohara, H. Ikeda, T. Ueno, T. Honma, A. Katoh, K. Sasaki, T. Shimada, Y. Oike and T. Imaizumi: Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103, 2776-2779 (2001)
doi:10.1161/hc2301.092122
177 C. Heeschen, R. Lehmann, J. Honold, B. Assmus, A. Aicher, D. H. Walter, H. Martin, A. M. Zeiher and S. Dimmeler: Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 109, 1615-1622 (2004)
doi:10.1161/01.CIR.0000124476.32871.E3
178 P. P. Huang, S. Z. Li, M. Z. Han, Z. J. Xiao, R. C. Yang, L. G. Qiu and Z. C. Han: Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost 91, 606-609 (2004) doi:10.1160/TH03-06-0343
179 P. P. Huang, S. Li, M. Han, Z. Xiao, R. Yang and Z. C. Han: Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28, 2155-2160 (2005)
doi:10.2337/diacare.28.9.2155
180 B. Zhou, M. C. Poon, W. T. Pu and Z. C. Han: Therapeutic neovascularization for peripheral arterial diseases: advances and perspectives. Histol Histopathol 22, 677-686 (2007)

181 C. Rouget: Memoire sur le development, la structure et les proprietes physiologiques des capillaires sanguins et lymphatiques. Arch Physiol Norm Pathol 5, 603-663 (1873)

182 K. W. Zimmermann: Der feinere Bau der Blutcapillares. Z Anat Entwicklungsgesch 68, 3-109 (1923)
doi:10.1007/BF02593544
183 L. Diaz-Flores, R. Gutierrez, H. Varela, N. Rancel and F. Valladares: Microvascular pericytes: A review of their morphological and functional characteristics. Histol Histopathol 6: 269-286 (1991)

184 C. T. Brighton, D. G. Lorich, R. Kupcha, T. M. Reilly, A. R. Jones and R. A. Woodbury: The pericyte as a possible osteoblast progenitor cell. Clin Orthop Relat Res 275, 287-299 (1992)

185 V. Nehls, K. Denzer, D. Drenckhahn: Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270, 469-474 (1992)
doi:10.1007/BF00645048
186 M. C. Galmiche, V. E. Koteliansky, J. Briere, P. Herve and P. Charbord: Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Blood 82, 66-76 (1993)

187 M. J. Doherty, B. A. Ashton, S. Walsh, J. N. Beresford, M. E. Grant and A. E. Canfield: Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13, 828-838 (1998)
doi:10.1359/jbmr.1998.13.5.828
188 P. A. Zuk, M. Zhu, H. Mizuno, J. Huang, J. W. Futrell, A. J. Katz, P. Benhaim, H. P. Lorenz and M. H. Hedrick: Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng 7, 211-228 (2001)
doi:10.1089/107632701300062859
189 S. Shi and S. Gronthos: Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 18, 696-704 (2003)
doi:10.1359/jbmr.2003.18.4.696
190 A. C. Zannettino, S. Paton, A. Arthur, F. Khor, S. Itescu, J. M. Gimble and S. Gronthos: Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol 214, 413-421 (2008)
doi:10.1002/jcp.21210
191 C. Farrington-Rock, N. J. Crofts, M. J. Doherty, B. A. Ashton, C. Griffin-Jones and A. E. Canfield: Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110, 2226-2232 (2004)
doi:10.1161/01.CIR.0000144457.55518.E5
192 L. Díaz-Flores, E. Rodríguez, M. J. Gayoso and R. Gutiérrez: Growth of two types of cartilage after implantation of free autogeneic perichondrial grafts. Clin Orthop 234: 267-279 (1988)

193 S. Takahashi and M. R. Urist: Differentiation of cartilage on three substrata under the influence of an aggregate of morphogenetic protein and other bone tissue noncollagenous proteins (BMP/iNCP). Clin Orthop 207, 227-234 (1986)

194 A. M. Schor, T. D. Allen, A. E. Canfield, P. Sloan and S.L. Schor: Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci 97, 449-461 (1990)

195 L. Diaz-Flores, R. Gutierrez, A. Lopez-Alonso, R. Gonzalez and H. Varela: Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin Orthop 275, 280-286 (1992)

196 G. D. Collett and A. E. Canfield: Angiogenesis and pericytes in the initiation of ectopic calcification. Circ Res 96, 930-938 (2005)
doi:10.1161/01.RES.0000163634.51301.0d
197 R. L. Richardson, G. J. Hausman and D. R. Campion: Response of pericytes to thermal lesíon in the inguinal fat pad of 10-day-old rats. Acta Anat 114, 41-57 (1982)

198 H. Z. Movat and N. V. P. Fernando: The fine structure of the terminal vascular bed. IV. The venules and their perivascular cell (pericytes, adventitial cells). Exp Mol Pathol 3, 98-114 (1964)
doi:10.1016/0014-4800(64)90044-9
199 Díaz-Flores and C. Domínguez. Relation between arterial intimal thickening and the vasa-vasorum. Virchows Arch (A) 406, 165-177 (1985)
doi:10.1007/BF00737083
200 G. I. Schoefl: Studies on inflammation. III. Growing capillaries: their structure and permeability. Virchows Arch Pathol Anat Physiol Klin Med 337,97-141 (1963)

201 P. C. Burger and G. K. Klintworth: Autoradiographic study of corneal neovascularization induced by chemical cautery. Lab Invest 45, 328-35 (1981)

202 L. Díaz-Flores, R. Gutiérrez, P. Gonzalez and H. Varela. Inducible perivascular cells contribute to the neochondrogenesis in grafted perichondrium. Anat Rec 229, 1-8 (1991)
doi:10.1002/ar.1092290102
203 L. Díaz-Flores, F. Valladares, R. Gutiérrez and H. Varela: The role of the pericytes of the adventitial microcirculation in the arterial intimal thickening. Histol Histopathol 5, 145-153 (1990)

204 L. Díaz-Flores Jr, J. F. Madrid, R. Gutiérrez, H. Varela, F. Valladares and L. Díaz-Flores: Cell contribution of vasa-vasorum to early arterial intimal thickening formation. Histol Histopathol 22, 1379-1386 (2007)

205 B. Brachvogel, H. Moch, F. Pausch, U. Schlotzer-Schrehardt, C.Hofmann, R. Hallmann, K. von der Mark, T. Winkler and E. Poschl: Perivascular cells expressing annexin A5 define a novel mesenchymal stem cell-like population with the capacity to differentiate into multiple mesenchymal lineages. Development 132, 2657-2668 (2005)
doi:10.1242/dev.01846
206 S. Christian, R. Winkler, I. Helfrich, A. M. Boos, E. Besemfelder, D. Schadendorf and H. G. Augustin: Endosialin (tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol 172, 486-494 (2008)
doi:10.2353/ajpath.2008.070623
207 N. Simonavicius, D. Robertson, D. A. Bax, C. Jones, I. J. Huijbers and C. M. Isacke: Endosialin (CD248) is a marker of tumor-associated pericytes in high-grade glioma. Mod Pathol (advance online publication 11 January) (2008)

208 S. Gronthos, A. C. Zannettino, S. J. Hay, S. Shi, S. E. Graves, A. Kortesidis and P. J. Simmons: Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci 116, 1827-1835 (2003)
doi:10.1242/jcs.00369
209 H. Lovschall, T. A. Mitsiadis, K. Poulsen, K. H. Jensen and A. L. Kjeldsen: Coexpression of Notch3 and Rgs5 in the pericyte-vascular smooth muscle cell axis in response to pulp injury. Int J Dev Biol 51, 715-721 (2007)
doi:10.1387/ijdb.072393hl
210 H. E. Young, T. A. Steele, R. A. Bray, J. Hudson, J. A. Floyd, K. Hawkins, K. Thomas, T. Austin, C. Edwards, J. Cuzzourt, M. Duenzl, P. A. Lucas and A. C. Black Jr.: Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec 264, 51-62 (2001)
doi:10.1002/ar.1128
211 B. M. Seo, M. Miura, S. Gronthos, P. M. Bartold, S. Batouli, J. Brahim, M. Young, P. G. Robey, C. Y. Wang and S. Shi: Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364, 149-155 (2004)
doi:10.1016/S0140-6736(04)16627-0
212 D. O. Traktuev, S. Merfeld-Clauss, J. Li, M. Kolonin, W. Arap, R. Pasqualini, B. H. Johnstone and K. L. March: A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 102, 77-85 (2008)
doi:10.1161/CIRCRESAHA.107.159475
213 J. P. Kirton, N. J. Crofts, S. J. George, K. Brennan and A. E. Canfield: Wnt/beta-catenin signaling stimulates chondrogenic and inhibits adipogenic differentiation of pericytes: potential relevance to vascular disease? Circ Res 101, 581-589 (2007)
doi:10.1161/CIRCRESAHA.107.156372
214 L. Díaz-Flores, A. I. Martín, R. García and R. Gutiérrez: Proliferative Fasciitis: Ultrastructure and Histogenesis. J Cutan Pathol 16, 85-92 (1989)
doi:10.1111/j.1600-0560.1989.tb00016.x
215 L. Díaz-Flores, A. I. Martín Herrera, R. Garcia Montelongo and R. Gutiérrez: Role of pericytes and endothelial cells in tissue repair and related pathological processes. J Cutan Pathol 17, 191-192 (1990)
doi:10.1111/j.1600-0560.1990.tb00082.x
216 H. Iwasaki, T. Isayama, H. Johzaki and M. Kikuchi: Malignant fibrous histiocytoma. Evidence of perivascular mesenchymal cell origin. Immunocytochemical studies with monoclonal anti-MFH antibodies. Am J Pathol 128, 528-537 (1987)

217 J. W. Bolen and D. Thoming: Benign lipoblastoma and mixoid liposarcoma. A comparative light- and electronmicroscopic study. Am J Surg Pathol 4, 163-174 (1980)

218 R. G. Bagley, W. Weber, C. Rouleau and B. A. Teicher: Pericytes and endothelial precursor cells: cellular interactions and contributions to malignancy. Cancer Res 65, 9741-9750 (2005)
doi:10.1158/0008-5472.CAN-04-4337
219 I. Rajantie, M. Ilmonen, A. Alminaite, U. Ozerdem, K. Alitalo and P. Salven: Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104, 2084-2086 (2004)
doi:10.1182/blood-2004-01-0336
220 T. Ziegelhoeffer, B. Fernandez, S. Kostin, M. Heil, R. Voswinckel, A. Helisch and W. Schaper: Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 94, 230-238 (2004)
doi:10.1161/01.RES.0000110419.50982.1C
221 U. Ozerdem, K. Alitalo, P. Salven and A. Li: Contribution of bone marrow-derived pericyte precursor cells to corneal vasculogenesis. Invest Ophthalmol Vis Sci 46, 3502-3506 (2005)
doi:10.1167/iovs.05-0309
222 T. Asahara and J. M. Isner: Endothelial progenitor cells for vascular regeneration. J Hematother Stem Cell Res 11, 171-178 (2002)
doi:10.1089/152581602753658385
223 T. Asahara: Endothelial progenitor cells for neovascularization. Ernst Schering Res Found Workshop 43, 211-216 (2003)

224 T. Asahara and A. Kawamoto: Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol 287, C572-C579 (2004)
doi:10.1152/ajpcell.00330.2003
225 E. Kokovay, L. Li and L. A. Cunningham: Angiogenic recruitment of pericytes from bone marrow after stroke. Cereb Blood Flow Metab 26, 545-555 (2006)
doi:10.1038/sj.jcbfm.9600214
226 S. Song, A. J. Ewald, W. Stallcup, Z. Werb and G. Bergers: PDGFRbeta+ perivascular progenitor cells in tumors regulate pericyte differentiation and vascular survival. Nat Cell Biol 7, 870-879 (2005)
doi:10.1038/ncb1288
227 S. R. Bababeygy, S. H. Cheshier, L. C. Hou, D. M. Higgins, I. L. Weissman and V. C. Tse: Hematopoietic Stem Cell-Derived Pericytic Cells in Brain Tumor Angio-Architecture. Stem Cells Dev 17, 11-18 (2008)
doi:10.1089/scd.2007.0117
228 K. M. Howson, A. C. Aplin, M. Gelati, G. Alessandri, E. A. Parati and R. F. Nicosia: The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture. Am J Physiol Cell Physiol 289, C1396-C1407 (2005)
doi:10.1152/ajpcell.00168.2005
229 D. W. Powell, R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I. Saada and A. B. West: Myofibroblasts, I: paracrine cells important in health and disease. Am J Physiol 277, C1-C9 (1999)

230 B. Eckes, P. Zigrino, D. Kessler, O. Holtkötter, P. Shephard, C. Mauch and T. Krieg: Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol 19, 325-332 (2000)
doi:10.1016/S0945-053X(00)00077-9
231 J. J. Tomasek, G. Gabbiani, B. Hinz, C. Chaponnier, R. A. Brown: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3, 349-363 (2002)
doi:10.1038/nrm809
232 G. Gabbiani: The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200, 500-503 (2003)
doi:10.1002/path.1427
233 H. Bouissou, M. Pieraggi, M. Julian, D. Uhart and J. Kokolo: Fibroblasts in dermal tissue repair. Electron microscopic and immunohistochemical study. Int J Dermatol 27, 564-570 (1988)

234 I. Darby, O. Skalli and G. Gabbiani: Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 63, 21-29 (1990)

235 R. A. Clark: Fibrin and wound healing. Ann N Y Acad Sci 936, 355-367 (2001)

236 I.A. Darby and T.D. Hewitson: Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 257, 143-179 (2007)
doi:10.1016/S0074-7696(07)57004-X
237 J. Xu and R. A. F. Clark: Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 132, 239-249 (1996)
doi:10.1083/jcb.132.1.239
238 P. Mignatti, D. B. Rifkin, H. G. Welgus, W. C. Parks: Proteinases and tissue remodeling. In: R. A. F. Clark, ed. The molecular and cellular biology of wound repair. 2nd ed.: Plenum Press. New York. pp. 427-74 1996

239 M. Vaalamo, L. Mattila, N. Johansson, A. L. Kariniemi, M. L. Karjalainen-Lindsberg, V. M. Kähäri and U. Saarialho-Kere: Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 109, 96-101 (1997)
doi:10.1111/1523-1747.ep12276722
240 M. P. Welch, G. F. Odland, R. A. F. Clark: Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J Cell Biol 110, 133-145 (1990)
doi:10.1083/jcb.110.1.133
241 R. A. F. Clark, L. D. Nielsen, M. P. Welch and J. M. McPherson: Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to TGF-ß. J Cell Sci 108, 1251-1261 (1995)

242 A. B. Roberts and M. B. Sporn: Transforming growth factor-ß. In: R. A. F. Clark, ed. The molecular and cellular biology of wound repair. 2nd ed. Plenum Press. New York. pp 275-308 (1996)

243 C-H. Heldin and B. Westermark: Role of platelet-derived growth factor in vivo. In: R.A.F. Clark, ed. The molecular and cellular biology of wound repair. 2nd ed. Plenum Press. New York. pp: 249-273 (1996)

244 W. S. Kim, B. S. Park, J. H. Sung, J. M. Yang, S. B. Park, S. J. Kwak and J. S. Park: Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci 48, 15-24 (2007)
doi:10.1016/j.jdermsci.2007.05.018
245 K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda and S. Yamanaka: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 (2007)
doi:10.1016/j.cell.2007.11.019
246 S. Yamanaka: Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif 41 Suppl 1, 51-56 (2008)

247 M. van Amerongen, G. Bou-Gharios, E. Popa, J. van Ark, A. Petersen, G. van Dam, M. van Luyn and M. Harmsen: Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol 214, 377-386 (2008)
doi:10.1002/path.2281
248 A. J. Friedenstein, R. K. Chailakhjan and K. S. Lalykina: The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3, 393-403 (1970)

249 E. A. Luria, A. F. Panasyuk and A. Y. Friedenstein: Fibroblast colony formation from monolayer cultures of blood cells. Transfusion 11, 345-349 (1971)

250 A. J. Friedenstein, U. F. Deriglasova, N. N. Kulagina, A. F. Panasuk, S. F. Rudakowa, E. A. Luriá and I. A. Ruadkow: Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2, 83-92 (1974)

251 M. Owen and A. J. Friedenstein: Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 136, 42-60 (1988)

252 A. J. Friedenstein: Determined and inducible osteogenic precursor cells. In: Hard Tissue Growth, Repair and Remineralization, vol. 11. Elsevier. pp 169-185. Amsterdam (1973)

253 M. Reyes, T. Lund, T. Lenvik, D. Aguiar, L. Koodie and C. M. Verfaillie: Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98, 2615-2625 (2001)
doi:10.1182/blood.V98.9.2615
254 R. F. Pereira, K. W. Halford, M. D. O'Hara, D. B. Leeper, B. P. Sokolov, M. D. Pollard, O. Bagasra, and D. J. Prockop: Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92, 4857-4861 (1995)
doi:10.1073/pnas.92.11.4857
255 J. H. Campbell, C. L. Han and G. R. Campbell: Neointimal formation by circulating bone-marrow cells. Ann NY Acad Sci 947, 18-24 (2001)

256 K. Stewart, S. Walsh, J. Screen, C. M. Jefferiss, J. Chainey, G. R. Jordan and J. N. Beresford: Further characterization of cells expressing STRO-1 in cultures of adult human bone marrow stromal cells. J Bone Miner Res 14, 1345-1356 (1999)
doi:10.1359/jbmr.1999.14.8.1345
257 S. Walsh, C. Jefferiss, K. Stewart, G. R. Jordan, J. Screen and J. N. Beresford: Expression of the developmental markers STRO-1 and alkaline phosphatase incultures of human marrow stromal cells: regulation by fibroblast growth factor (FGF)-2 and relationship to the expression of FGF receptors 1-4 Bone 27, 185-195 (2000)
doi:10.1016/S8756-328(00)00319-7

258 P. Bianco and P. Gehron Robey: Marrow stromal stem cells. J Clin Invest 105, 1663-1668 (2000)
doi:10.1172/JCI10413
259 A. Abderrahim-Ferkoune, O. Bezy, S. Astri-Roques, C. Elabd, G. Ailhaud and E. Z. Amri: Trans-differentiation of preadipose cells into smooth muscle-like cells: role of aortic carboxypeptidase-like protein. Exp Cell Res 293, 219-228 (2004)
doi:10.1016/j.yexcr.2003.10.020
260 S. Ahdjoudj, O. Fromigue and P. J. Marie: Plasticity and regulation of human bone marrow stromal osteoprogenitor cells: potential implication in the treatment of age-related bone loss. Histol Histopathol 19, 151-157 (2004)

261 J. H. Bennett, C. J. Joyner, J. T. Triffitt and M. E. Owen: Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci 99, 131-139 (1991)

262 R. F. Pereira, M. D. O'Hara, A. V. Laptev, K. W. Halford, M. D. Pollard, R. Class, D. Simon, K. Livezey and D. J. Prockop: Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 95, 1142-1147 (1998)
doi:10.1073/pnas.95.3.1142
263 J. E. Dennis, A. Merriam, A. Awadallah, J. U. Yoo, B. Johnstone and A. I. Caplan: A quadripotential mesenchymal progenitor cell isolated from the marrow of an adult mouse. J Bone Miner Res 14, 700-709 (1999)
doi:10.1359/jbmr.1999.14.5.700
264 C. Toma, M. F. Pittenger, K. S. Cahill, B. J. Byrne and P. D. Kessler: Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105, 93-98 (2002)
doi:10.1161/hc0102.101442
265 Y. Jiang, B. Vaessen, T. Lenvik, M. Blackstad, M. Reyes and C. Verfaillie: Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 30, 896-904 (2002b)
doi:10.1016/S0301-472X(02)00869-X
266 M. F. Pittenger and B. J. Martin: Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95, 9-20 (2004)
doi:10.1161/01.RES.0000135902.99383.6f
267 M. H. Mankani, S. A. Kuznetsov, R. M. Wolfe, G. W. Marshall and P.G. Robey: In vivo bone formation by human bone marrow stromal cells: reconstruction of the mouse calvarium and mandible. Stem Cells 24, 2140-2149 (2006)
doi:10.1634/stemcells.2005-0567
268 M. H. Mankani, S. A. Kuznetsov, B. Shannon, R. K. Nalla, R. O. Ritchie, Y. Qin and P. G. Robey: Canine cranial reconstruction using autologous bone marrow stromal cells. Am J Pathol 168, 542-550 (2006)
doi:10.2353/ajpath.2006.050407
269 K. Tamama, V. H. Fan, L. G. Griffith, H. C. Blair and A. Wells: Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells. Stem Cells 24, 686-695 (2006)
doi:10.1634/stemcells.2005-0176
270 K. C. Hicok, T. Thomas, F. Gori, D. J. Rickard, T. C. Spelsberg and B. L. Riggs: Development and characterization of conditionally immortalized osteoblast precursor cell lines from human bone marrow stroma. J Bone Miner Res 13, 205-217 (1998)
doi:10.1359/jbmr.1998.13.2.205
271 S. Ahdjoudj, F. Lasmoles, B. O. Oyajobi, A. Lomri, P. Delannoy and P. J. Marie: Reciprocal control of osteoblast/chondroblast and osteoblast/adipocyte differentiation of multipotential clonal human marrow stromal F/STRO-1(+) cells. J Cell Biochem 81, 23-38 (2001)
doi:10.1002/1097-4644(20010401)81:1<23::AID-JCB1021>3.0.CO;2-H
272 C. Shui, T. C. Spelsberg, B. L. Riggs and S. Khosla: Changes in Runx2/Cbfa1 expression and activity during osteoblastic differentiation of human bone marrow stromal cells. J Bone Miner Res. 18, 213-221 (2003)
doi:10.1359/jbmr.2003.18.2.213
273 H. Qi, D. J. Aguiar, S. M. Williams, A. La Pean, W. Pan and C. M. Verfaillie: Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells. Proc Natl Acad Sci USA 100, 3305-3310 (2003)
doi:10.1073/pnas.0532693100
274 S. J. Zhu, B. H. Choi, J. Y. Huh, J. H. Jung, B. Y. Kim and S. H. Lee: A comparative qualitative histological analysis of tissue-engineered bone using bone marrow mesenchymal stem cells, alveolar bone cells, and periosteal cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101, 164-169 (2006)
doi:10.1016/j.tripleo.2005.04.006
275 R. Bucala, L. A. Spiegel, J. Chesney, M. Hogan and A. Cerami: Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1, 71-81 (1994)

276 J. Chesney, C. Metz, A. B. Stavitsky, M. Bacher and R. Bucala: Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160, 419-425 (1998)

277 R. Abe, S. C. Donnelly, T. Peng, R. Bucala and C. N. Metz: Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166, 7556-7562 (2001)

278 L. Yang, P. G. Scott, J. Giuffre, H. A. Shankowsky, A. Ghahary and E. E. Tredget: Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 82, 1183-1192 (2002)

279 D. Pilling, C. D. Buckley, M. Salmon and R. H. Gomer: Inhibition of fibrocyte differentiation by serum amyloid P J Immunol 171, 5537-5546 (2003)

280 J. Chesney, M. Bacher, A. Bender and R. Bucala: The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA 94, 6307-6312 (1997)
doi:10.1073/pnas.94.12.6307
281 L. Yang, P. G. Scott, C. Dodd, A. Medina, H. Jiao, H. A. Shankowsky, A. Ghahary and E. E. Tredget: Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 13, 398-404 (2005)
doi:10.1111/j.1067-1927.2005.130407.x
282 D. Pilling, N. M. Tucker and R.H. Gomer: Aggregated IgG inhibits the differentiation of human fibrocytes. J Leukoc Biol 79, 1242-1251 (2006)
doi:10.1189/jlb.0805456
283 L. Mori, A. Bellini, M. A. Stacey, M. Schmidt and S. Mattoli: Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 304, 81-90 (2005)
doi:10.1016/j.yexcr.2004.11.011
284 M. Schmidt, G. Sun, M. A. Stacey, L. Mori and S. Mattoli: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171, 380-389 (2003)

285 K. M. Hong, M. D. Burdick, R. J. Phillips, D. Heber and R. M. Strieter: Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. FASEB J 19, 2029-2031 (2005)

286 C. Balmelli, N. Ruggli, K. McCullough and A. Summerfield: Fibrocytes are potent stimulators of anti-virus cytotoxic T cells. J Leukoc Biol 77, 923-933 (2005)
doi:10.1189/jlb.1204701
287 A. Bellini and S. Mattoli: The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest 87, 858-870 (2007)
doi:10.1038/labinvest.3700654
288 B. B. Moore, J. E. Kolodsick, V. J. Thannickal, K. Cooke, T. A. Moore, C. Hogaboam, C. A. Wilke, and G. B. Toews: CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 166, 675-684 (2005)

289 P. J. Barth and C. Westhoff: CD34+ Fibrocytes: Morphology, Histogenesis and Function. Cur Stem Cell Res & Therapy 2, 221-227 (2007)

290 D.J. Grab, H. Lanners, L.N. Martin, J. Chesney, C. Cai, H.D. Adkisson and R. Bucala.: Interaction of Borrelia burgdorferi with peripheral blood fibrocytes, antigen-presenting cells with the potential for connective tissue targeting. Mol Med 5, 46-54 (1999)

291 I. Hartlapp, R. Abe, R. W. Saeed, T. Peng, W. Voelter, R. Bucala and C. N. Metz: Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J 15, 2215-2224 (2001)
doi:10.1096/fj.01-0049com
292 L. C. Rogers, N. J. Bevilacqua and D. G. Armstrong: The use of marrow-derived stem cells to accelerate healing in chronic wounds. Int Wound J (Epub ahead of print) 2008

293 Y. P. Li, S. Paczesny, E. Lauret, S. Poirault, P. Bordigoni, F. Mekhloufi, O. Hequet, Y. Bertrand, J. P. Ou-Yang, J. F. Stoltz, P. Miossec and A. Eljaafari: Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J Immunol 180, 1598-1608 (2008)

294 J. Folkman: Angiogenesis and angiogenesis inhibition: an overview. EXS 79, 1-8 (1997)

295 N. Guo, H. C. Krutzsch, J. K. Inman and D. D. Roberts: Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res 57, 1735-1742 (1997)

296 G. Gabbiani, C. Chaponnier and I. Huttner: Cytoplasmic filaments and gap junctions in epithelial cells and myofibroblasts during wound healing. J Cell Biol 76, 561-568 (1978)
doi:10.1083/jcb.76.3.561
297 M. Madlener, W.C. Parks and S. Werner: Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res 242, 201-210 (1998)
doi:10.1006/excr.1998.4049
298 A. E. Grigoriadis, J. N. Heersche and J. E. Aubin: Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone-derived clonal cell population. J Cell Biol 106, 2139-2151 (1988)
doi:10.1083/jcb.106.6.2139
299 Y. Tintut, F. Parhami, K. Boström, S. M. Jackson and L. L. Demer: cAMP stimulates osteoblast-like differentiation of calcifying vascular cells. J Biol Chem 273, 7547-7553 1998
doi:10.1074/jbc.273.13.7547
300 M. F. Pittenger, A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig and D. R. Marshak: Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147 (1999)
doi:10.1126/science.284.5411.143
301 P. A. Zuk, M. Zhu, P. Ashjian, D. A. De Ugarte, J. I. Huang, H. Mizuno, Z. C. Alfonso, J. K. Fraser, P. Benhaim and M. H. Hedrick: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13, 4279-4295 (2002)
doi:10.1091/mbc.E02-02-0105
302 A. Winter, S. Breit, D. Parsch, K. Benz, E. Steck, H. Hauner, R. M. Weber, V. Ewerbeck and W. Richter: Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. Arthritis Rheum 48, 418-429 (2003)
doi:10.1002/art.10767
303 A. J. Leo and D. A. Grande: Mesenchymal stem cells in tissue engineering. Cells Tis Rep 183, 112-122 (2006) doi:10.1159/000095985
304 S. Heydarkhan-Hagvall, K. Schenke-Layland, J. Q. Yang, S. Heydarkhan, Y. Xu, P. A. Zuk, W. R. Maclellan and R. E. Beygui: Human Adipose Stem Cells: A Potential Cell Source for Cardiovascular Tissue Engineering. Cells Tis Org (Epub ahead of print) (2008)

305 G. S. Tjabringa, B. Zandieh-Doulabi, M. N. Helder, M. Knippenberg, P. I. Wuisman, J. Klein-Nulend, G. S. Tjabringa and B. Zandieh-Doulabi: The polymine spermine regulates osteogenic differentiation in adipose stem cells. J Cell Mol Med (Epub ahead of print) (2008)
doi:10.1111/j.1582-4934.2008.00224.x
306 K. H. Wang, A. P. Kao, H. Wangchen, F. Y. Wang, C. H. Chang, C. C. Chang and S. D. Lin: Optimizing proliferation and characterization of multipotent stem cells from porcine adipose tissue. Biotechnol Appl Biochem (Epub ahead of print) (2008)
doi:10.1042/BA20070201
307 L. E. Zaragosi, B. Wdziekonski, C. Fontaine, P. Villageois, P. Peraldi and C. Dani: Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes. BMC Cell Biol (Epub ahead of print) (2008)
doi:10.1186/1471-2121-9-11
308 K. M. Safford, K. C. Hicok, S. D. Safford, Y. D. Halvorsen, W. O. Wilkison, J. M. Gimble and H. E. Rice: Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun 294, 371-379 (2002).
doi:10.1016/S0006-291X(02)00469-2
309 Y. Xu, Z. Liu, L. Liu, C. Zhao, F. Xiong, C. Zhou, Y. Li, Y. Shan, F. Peng and C. Zhang: Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro. BMC Neurosci (Epub ahead of print) (2008)
doi:10.1186/1471-2202-9-21
310 S. Chen, Q. Zhang, X. Wu, P. G. Schultz and S. Ding: Dedifferentiation of lineage-committed cells by a small molecule. J Am Chem Soc 126, 410-411 (2004)
doi:10.1021/ja037390k, doi:10.1021/ja038081x, doi:10.1021/ja039107n,doi:10.1021/ja0381611
doi:10.1021/ja038945e, doi:10.1021/ja038702m
doi:10.1021/ja0383975, doi:10.1021/ja039355j
doi:10.1021/ja039031v, doi:10.1021/ja0396145
doi:10.1021/ja0490469, doi:10.1021/ja039829e
doi:10.1021/ja0390911, doi:10.1021/ja036491f
doi:10.1021/ja037389l
311 M. A. Eglitis and E. Mezey: Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94, 4080-4085 (1997)
doi:10.1073/pnas.94.8.4080
312 S. Corti, F. Locatelli, C. Donadoni, S. Strazzer, S. Salani, R. Del Bo, M. Caccialanza, N. Bresolin, G. Scarlato and G. P. Comi: Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia. J Neurosci Res 70, 721-733 (2002a)
doi:10.1002/jnr.10455
313 S. Corti, F. Locatelli, S. Strazzer, S. Salani, R. Del Bo, D. Soligo, P. Bossolasco, N. Bresolin, G. Scarlato and G. P. Comi: Modulated generation of neuronal cells from bone marrow by expansion and mobilization of circulating stem cells with in vivo cytokine treatment. Exp Neurol 177 443-452 (2002b)
doi:10.1006/exnr.2002.8004
314 S. Corti, F. Locatelli, C. Donadoni, M. Guglieri, D. Papadimitriou, S. Strazzer, R. Del Bo and G. P. Comi: Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain 127, 2518-2532 (2004)
doi:10.1093/brain/awh273
315 J. G. Toma and M. Akhavan, K. J. Fernandes, F. Barnabé-Heider, A. Sadikot, D. R. Kaplan and F. D. Miller: Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 3, 778-784 (2001)
doi:10.1038/ncb0901-778
316 S. Corti, F. Locatelli, D. Papadimitriou, S. Strazzer, S. Bonato and G. P. Comi: Nuclear reprogramming and adult stem cell potential. Histol Histopathol 20, 977-986 (2005)

317 A. Vignery: Osteoclasts and giant cells: macrophage-macrophage fusion mechanism. Int J Exp Pathol 81, 291-304 (2000)
doi:10.1111/j.1365-2613.2000.00164.x, doi:10.1046/j.1365-2613.2000.00164.x
318 G. R. Cunha and Y. K. Hom: Role of mesenchymal-epithelial interactions in mammary gland development. J Mammary Gland Biol Neoplasia 1, 21-35 (1996)
doi:10.1007/BF02096300
319 M. I. Gallego, N. Binart, G. W. Robinson, R. Okagaki, K. T. Coschigano, J. Perry, J. J. Kopchick, T. Oka, P. A. Kelly and L. Hennighausen: Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol 229, 163-175 (2001)
doi:10.1006/dbio.2000.9961

320 T. Sakakura, Y. Nishizuka and C. J. Dawe: Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland. Science 194, 1439-1441 (1976)
doi:10.1126/science.827022
321 J. F. Wiesen, P. Young, Z. Werb and G. R. Cunha: Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 126, 335-344 (1999)

322 E. J. Suuronen, J. P. Veinot, S. Wong, V. Kapila, J. Price, M. Griffith, T. G. Mesana and M. Ruel: Tissue-engineered injectable collagen-based matrices for improved cell delivery and vascularization of ischemic tissue using CD133+ progenitors expanded from the peripheral blood. Circulation 114, (Suppl):I138-44 (2006)
doi:10.1161/CIRCULATIONAHA.105.001081
323 A. Wenger, N. Kowalewski, A. Stahl, A. T. Mehlhorn, H. Schmal, G. B. Stark and G. Finkenzeller: Development and characterization of a spheroidal coculture model of endothelial cells and fibroblasts for improving angiogenesis in tissue engineering. Cells Tissues Organs 181, 80-88 (2005)
doi:10.1159/000091097
324 M. W. Laschke, Y. Harder, M. Amon, I. Martin, J. Farhadi, A. Ring, N. Torio-Padron, R. Schramm, M. Rücker, D. Junker, J. M. Häufel, C. Carvalho, M. Heberer, G. Germann, B. Vollmar and M. D. Menger: Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng 12, 2093-2104 (2006)
doi:10.1089/ten.2006.12.2093
325 K. A. Wieghaus, S. M. Capitosti, C. R. Anderson, P. J. Price, B. R. Blackman, M. L. Brown and E. A. Botchwey: Small molecule inducers of angiogenesis for tissue engineering. Tissue Eng 12, 1903-1913 (2006)
doi:10.1089/ten.2006.12.1903
326 F. Bianchi, M. Rosi, G. Vozzi, C. Emanueli, P. Madeddu and A. Ahluwalia: Microfabrication of fractal polymeric structures for capillary morphogenesis: Applications in therapeutic angiogenesis and in the engineering of vascularized tissue. J Biomed Mat Res: App Biomat 81B, 462-468 (2007)
doi:10.1002/jbm.b.30685
327 J. A. Rophael, R. O. Craft, J. A. Palmer, A. J. Hussey, G. P. Thomas, W. A. Morrison, A. J. Penington and G. M. Mitchell: Angiogenic growth factor synergism in a murine tissue engineering model of angiogenesis and adipogenesis. Am J Pathol 171, 2048-2057 (2007)
doi:10.2353/ajpath.2007.070066
328 D. W. Hutmacher and S. Cool: Concepts of scaffold-based tissue engineering--the rationale to use solid free-form fabrication techniques. J Cell Mol Med 11, 654-669 (2007)
doi:10.1111/j.1582-4934.2007.00078.x
329 C. W. Patrick, P. B. Chauvin, J. Hobley and G. P. Reece: Preadipocyte seeded PLGA scaffolds for adipose tissue engineering. Tissue Eng 5, 139-51 (1999)
doi:10.1089/ten.1999.5.139
330 C. W. Patrick Jr, B. Zheng, C. Johnston and G. P. Reece: Long-term implantation of preadipocyte-seeded PLGA scaffolds. Tissue Eng 8, 283-293 (2002)
doi:10.1089/107632702753725049
331 L. Díaz-Flores, M.J. Gayoso, J. Aneiros, G. Sanchez y T. Caballero: Histogénesis de los elementos que constituyen la pared de los vasos neoformados en los trombos organizados y recanalizados. Morf Norm Patol (A) 1: 217-230 (1977)

332 D. Lee, I. Yuki, Y. Murayama, A. Chiang, I. Nishimura, H. V. Vinters, C. J. Wang, Y. L. Nien, A. Ishil, B. M. Wu and F. Viñuela: Thrombus organization and healing in the swine experimental aneurysm model. Part I. A histological and molecular analysis. J Neurosurg 107, 94-108 (2007)
doi:10.3171/JNS-07/07/0094
333 J. Humphries, C. L. McGuinness, A. Smith, M. Waltham, R. Poston and K. G. Burnand: Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. J Vasc Surg 30, 894-899 (1999)
doi:10.1016/S0741-5214(99)70014-5
334 T. J. Fahey III, A. Sadaty, W. G. Jones 2nd, A. Barber, B. Smoller and G. T. Shires: Diabetes impairs the late inflammatory response to wound healing. J Surg Res 50, 308-313 (1991)
doi:10.1016/0022-4804(91)90196-S
335 M. A. Loots, E. N. Lamme, J. Zeegelaar, J. R. Mekkes, J. D. Bos and E. Middelkoop: Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 111, 850-857 (1998)
doi:10.1046/j.1523-1747.1998.00381.x
336 S. M. Levenson, E. F. Geever, L. V. Crowley, J. F. Oates3rd, C. W. Berard and H. Rosen: The healing of rat skin wounds. Ann Surg 161, 293-308 (1965)

337 M. Machesney, N. Tidman, A. Waseem, L. Kirby and I Leigh: Activated keratinocytes in the epidermis of hypertrophic scars. Am J Pathol 152, 1133-1141 (1998)

338 G. M. Saed, D. Ladin, J. Olson, X. Han, Z. Hou and D. Fivenson: Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol 134, 963-967 (1968)
doi:10.1001/archderm.134.8.963
339 S. Aiba and H. Tagami: Inverse correlation between CD34 expression and proline-4-hydroxylase immunoreactivity on spindle cells noted in hypertrophic scars and keloids. J Cutan Pathol 24, 65-69 (1997)
doi:10.1111/j.1600-0560.1997.tb01098.x
340 S. Yamagami, Y. Tokuda, K. Ishii, H. Tanaka and N. Endo: cDNA cloning and functional expression of a human monocyte chemoattractant protein 1 receptor. Biochem Biophys Res Commun 202, 1156-1162 (1994)
doi:10.1006/bbrc.1994.2049
341 T. Kurihara and R. Bravo: Cloning and functional expression of mCCR2, a murine receptor for the CC-chemokines JE and FIC. J Biol Chem 271, 11603-11607 (1996)
doi:10.1074/jbc.271.20.11603
342 P. Christensen, R. Goodman, L. Pastoriza, B. Moore and G. Toews: Induction of lung fibrosis in the mouse by intratracheal instillation of fluorescein isothiocyanate is not T-cell dependent. Am J Pathol 155, 1773-1779 (1999)

343 American Thoracic Society ERS: Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 161, 646-664 (2000)

344 B. B. Moore, L. Murray, A. Das, C. A. Wilke, A. B. Herrygers and G.B. Toews: The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol 35, :175-181. (2006)
doi:10.1165/rcmb.2005-0239OC
345 S. B. Wallach-Dayan and R. Golan-Gerstl: Evasion of myofibroblasts from immune surveillance: a mechanism for tissue fibrosis. Proc Natl Acad Sci USA 104, 20460-20465 (2007)
doi:10.1073/pnas.0705582104
346 V. Chaudhuri, L. Zhou and K. Karasek: Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol 34, 146-153 (2007)
doi:10.1111/j.1600-0560.2006.00584.x
347 P. Libby, P. M. Ridker and A Maseri: Inflammation and atherosclerosis. Circulation 105, 1135-1143 (2002)
doi:10.1161/hc0902.104353
348 R. Ross and J. Glomset: The pathogenesis of atherosclerosis. (first of two parts). N Engl J Med 295, 369-377 (1976a)

349 R. Ross and J. Glomset: The pathogenesis of atherosclerosis. (second of two parts). N Engl J Med 295, 420-425 (1976b)

350 R. Ross: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801-809 (1993)
doi:10.1038/362801a0
351 R. Ross: Atherosclerosis-an inflammatory disease. N Engl J Med 14: 340, 115-126 (1999)
doi:10.1056/NEJM199901143400207
352 A. Margariti, L. Zeng and Q. Xu: Stem cells, vascular smooth muscle cells and atherosclerosis. Histol Histopathol 21, 979-985 (2006)

353 O. Hassler: The origin of the cells constituting arterial intima thickening. an experimental autoradiographic study with the use of 3H-thymidine. Lab Invest 22, 286-293 (1970)

354 M.B. Stemerman and R. Ross: Experimental arteriosclerosis. I. Fibrous plaque formation in primates, an electron microscope study. J Exp Med 136, 769-7890 (1972)
doi:10.1084/jem.136.4.769
355 R. Ross and J. A. Glomset: Atherosclerosis and the arterial smooth muscle cell. proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180, 1332-1339 (1973)

356 L. Orcel, P. Hadjiisky and J. Roland: Réactivité histoenzymatique des cellules de l'épaississement diffus de l'intima de l'arterie fémorale envelopée d'un tube de polyéthyléne". Paroi Arterielle / Arterial Wall 2, 65-70 (1974)

357 S. Glagov and C. H. Ts'ao: Restitution of aortic wall after sustained necrotizing transmural ligation injury. role of blood cells and artery cells. Am. J Pathol 79, 7-30 (1975)

358 E. P. Benditt: Implications of the monoclonal character of human atherosclerotic plaques. Am J Pathol 86, 693-702 (1977)

359 J. Bhawan, I. Joris, U. Degirolami and G. Majno: Effect of occlusion on large vessels. Am J Pathol 88, 355-380 (1977)

360 M. B. Stemerman, T. H. Spaet, F. Pitlick, J. Cintron, I. Lejnieks and M. L. Thiel: The pattern of reendothelization and intimal thickening. Am J Pathol 87, 125-137 (1977)

361 A. Abou-Haila, P. Hadjiisky, J. Roland and L. Orcel: Etude histochimique et histoenzimatique de l'endartérite experimentales du lapin. I. L'endartérite fémorale". Paoi Artérielle / Arterial Wall. 4, 189-205 (1978).

362 A. W. Clowes, R. E. Collazo and W. J. Karnovsky: A morphologic and permeability study of luminal smooth muscle cells after arterial injury in the rat. Lab Invest 39, 141-150 (1978)

363 J. R. Guyton and M.J. Karnovsky. Smooth muscle cell proliferation in the occluded rat carotid artery. lack of requirement for luminal platelets. Am J Pathol 94, 585-602 (1979)

364 P. R. Potvliege and R. H. Bourgain: Thrombosis induced in vivo in the femoral artery of rats. an electron microscopic study of myointimal growth. Br J Exp Pathol 60, 382-388 (1979)

365 S.M. Schwartz, G.R. Campbell and J.H. Campbell: Replication of smooth muscle cells in vascular disease. Circ Res 58, 427-444 (1986)

366 R. G. Schaub, C. A. Rawlings and J. C. Keith: Platelet adhesion and myointimal proliferation in canine pulmonary arteries. Am J Pathol 140, 13-22 (1981)

367 W. S. Webster, S. P. Bishop and J. C. Geer. Experimental production of longitudinal smooth muscle cells in the intima of muscular arteries. Lab Invest 39, 370-374 (1974)

368 C.I. Han, G.R. Campbell and J.H. Campbell: Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res 38, 113-119 (2001)
doi:10.1159/000051038
369 S.M. Schwartz, E.R. O'Brien. and D. deBlois: Relevance of smooth muscle replication and development to vascular disease; In. Schwartz SM, Mercham, RP (eds): The vascular smooth muscel cell: Molecules and Biological Responses to the extracellular matrix. San Diego. Academic Press. pp. 81-139 (1995)

370 J. Buján, J. M. Bellón, M. C. Gianonatti and A. Golitsin: Intimal thickening in arterial autografts. Role of the adventitial layer. Histol Histopathol 7, 189-197 (1992)

371 S. Patel, Y. Shi, R. Niculescu, E. H. Chung, J. L. Martin and A. Zalewski: Characteristics of coronary smooth muscle cells and adventitial fibroblasts. Circulation 101, 524-532 (2000)

372 Y. Hu, Z. Zhang, E. Torsney, A.R. Afzal, F. Davison, B. Metzler and Q. Xu: Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113, 1258-1265 (2004)
doi:10.1172/JCI200419628, doi:10.1172/JCI19628
373 J. Herrmann, S. Samee, A. Chade, M. Rodriguez Porcel, L.O. Lerman and A. Lerman: Differential effect of experimental hypertension and hypercholesterolemia on adventitial remodeling. Arterioscler Thromb Vasc Biol 25, 447-453 (2005)
doi:10.1161/01.ATV.0000152606.34120.97
374 E. Torsney, Y. Hu, and Q. Xu: Adventitial progenitor cells contribute to arteriosclerosis. Trends Cardiovasc Med 15, 64-68 (2005)
doi:10.1016/j.tcm.2005.02.003
375 O. S. Plekhanova, M. Y. Men'shikov, P. P. Bashtrykov, B. C. Berk, V. A. Tkachuk, and E. V. Parfenova: Urokinase induces ROS production in vascular smooth muscle cells. Bull Exp Biol Med 142, 304-307 (2006)
doi:10.1007/s10517-006-0352-4
376 K. R. Stenmark, N. Davie, M. Frid, E. Gerasimovskaya and M. Das: Role of the adventitia in pulmonary vascular remodeling. Physiology 21, 134-145 (2006)
doi:10.1152/physiol.00053.2005
377 Y. Shi, M. Pieniek, A. Fard, J. O'Brien, J.D. Mannion and A. Zalewski: Adventitial remodeling after coronary arterial injury. Circulation 93, 340-348 (1996)

378 A. Hoshino, H. Chiba, K. Nagai, G. Ishii and A. Ochiai: Human vascular adventitial fibroblasts contain mesenchymal stem/progenitor cells. Biochem Biophys Commun 368, 305-310.

379 D. J. Prockop: Marrow stromal cells as stem cells for non-hematopoietic tissues. Science 276, 71-74 (1997)
doi:10.1126/science.276.5309.71
380 R. Bucala: Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol 5, 36-39 (2008)
doi:10.1016/j.jacr.2007.08.016
381 E. R. Andreeva, I. M. Pugach and A. N. Orekhov: Subendothelial smooth muscle cells of human aorta express macrophage antigen in situ and in vitro. Atherosclerosis 135, 19-27 (1997)
doi:10.1016/S0021-9150(97)00136-6
382 J. P. Fletcher, A. Guiffre and H. Medbury: Fibrocytes in atherosclerosis. VS022 ANZ J Surg 75, (Suppl.) A119 (2005)

383 H. Medbury: Role of fibrocytes in atherogenesis. Chapter 10 In R. Bucala (ed.) Fibrocytes: New insights into tissue repair and systemic fibroses. World Scientific Publishing Co. Pte. Ltd. pp. 175-194 (2007)

384 F. K. Swirski, P. Libby, E. Aikawa, P. Alcaide, F. W. Luscinskas, R. Weissleder and M. J. Pittet: Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117, 195-205 (2007)
doi:10.1172/JCI29950
385 M. J. Davies, P. D. Richardson, N. Woolf, D. R. Katz and J.: Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 69, 377-381 (1993)
doi:10.1136/hrt.69.5.377, doi:10.1136/hrt.69.1.3
doi:10.1136/hrt.69.1_Suppl.S62, doi:10.1136/hrt.69.1_Suppl.S1
doi:10.1136/hrt.69.1_Suppl.S3, doi:10.1136/hrt.69.1_Suppl.S29
doi:10.1136/hrt.69.2.114
386 E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. E. Koteliansky and M. J. Daemen: Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol 22, 975-982 (2002)
doi:10.1161/01.ATV.0000019729.39500.2F
387 Z. Gong and L. E. Niklason: Small-diameter human vessel wall engineered from bone marrow-derived mesenchymal stem cells (hMSCs). FASEB J Jan 18 (Epub ahead of print) (2008)

doi:10.1096/fj.07-087924
388 H. Li, X. Fan and J. Houghton: Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 101, 805-815 (2007)
doi:10.1002/jcb.21159
389 T. D. Tlsty and P.W. Hein: Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11, 54-59 (2001)
doi:10.1016/S0959-437X(00)00156-8
390 M. J. Bissell and D. Radisky: Putting tumors in context. Nat Rev Cancer 1, 46-54 (2001)
doi:10.1038/35094059
391 L.M. Coussens and Z Werb: Inflammation and cancer. Nature 420, 860-867 (2002)
doi:10.1038/nature01322
392 K. Le Blanc, I. Rasmusson, B. Sundberg, C. Götherström, M. Hassan, M. Uzunel and O. Ringdén: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439-1441 (2004)
doi:10.1016/S0140-6736(04)16104-7
393 M. M. Mueller and N. E. Fusenig: Friends or foes - bipolar effects of the tumor stroma in cancer. Nat Rev Cancer 4, 839-849 (2004)
doi:10.1038/nrc1477
394 B. Hall, M. Andreeff and F. Marini: The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb. Exp. Pharmacol 180, 263-283 (2007)

395 V. Hofmeister, D. Schrama and J.C. Becker: Anti-cancer therapies targeting the tumor stroma. Cancer Immunol Immunother 57, 1-17 (2008)
doi:10.1007/s00262-007-0365-5
396 K. Kurose, S. Hoshaw-Woodard, A. Adeyinka, S. Lemeshow, P.H. Watson and C.Eng: Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumor-microenvironment interactions. Hum Mol Genet 10, 1907-1913 (2001)
doi:10.1093/hmg/10.18.1907
397 P.A. Kenny and M.J. Bissell: Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107, 688-695 (2003)
doi:10.1002/ijc.11491
398 R. Hill, Y. Song, R. D. Cardiff and T. Van Dyke: Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 123, 1001-1011 (2005)
doi:10.1016/j.cell.2005.09.030
399 H. Tsushima, N. Ito, S. Tamura, Y. Matsuda, M. Inada, I. Yabuuchi, Y. Imai, R. Nagashima, H. Misawa, H. Takeda, Y. Matsuzawa and S. Kawata: Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 7, 1258-1262 (2001)

400 R. Kalluri: Basement membranes: structure, assembly and role in tumor angiogenesis. Nat Rev Cancer 3, 422-433 (2003)
doi:10.1038/nrc1094

401 M. Philip, D. A. Rowley and H. Schreiber: Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol 14, 433-439 (2004)
doi:10.1016/j.semcancer.2004.06.006
402 A. Boire, L. Covic, A. Agarwal, S. Jacques, S. Sherifi and A. Kuliopulos: PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303-313 (2005)
doi:10.1016/j.cell.2004.12.018
403 J. Pilch, D. M. Brown, M. Komatsu, T. A. Järvinen, M. Yang, D. Peters, R. M. Hoffman and E. Ruoslahti: Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci USA 103, 2800-2804 (2006)
doi:10.1073/pnas.0511219103
404 C. H. Stuelten, S. DaCosta Byfield, P. R. Arany, T. S. Karpova, W. G. Stetler-Stevenson and A. B. Roberts: Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta. J Cell Sci 118, 2143-2153 (2005)
doi:10.1242/jcs.02334
405 M. D. Sternlicht and Z. Werb. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17, 463-516 (2001)
doi:10.1146/annurev.cellbio.17.1.463
406 M. T. Dimanche-Boitrel, L. Vakaet L Jr, P. Pujuguet, B. Chauffert, M. S. Martin, A. Hammann, F. Van Roy, M. Mareel and F. Martin: In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of tumor-associated myofibroblasts. Int J Cancer 56, 512-521 (1994)
doi:10.1002/ijc.2910560410
407 L. Rønnov-Jessen, O. W. Petersen, V. E. Koteliansky and M. J. Bissell: The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95, 859-73 (1995)
doi:10.1172/JCI117736
408 M. Iwano, D. Plieth, T. M. Danoff, C. Xue, H. Okada and E. G. Neilson: Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110, 341-350 (2002)
doi:10.1172/JCI200215518, doi:10.1172/JCI15518
409 M. Studeny, F. C. Marini, R. E. Champlin, C. Zompetta, I. J. Fidler and M. Andreeff. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 62, 3603-3608 (2002)

410 N. C. Direkze, K. Hodivala-Dilke, R. Jeffery, T. Hunt, R. Poulsom, D. Oukrif, M. R. Alison and N. A. Wright: Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64, 8492-8495 (2004)
doi:10.1158/0008-5472.CAN-04-1708
411 M. Studeny, F. C. Marini, J. L. Dembinski, C. Zompetta, M. Cabreira-Hansen, B. N. Bekele, R. E. Champlin and M. Andreeff: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96, 1593-1603 (2004)

412 M. De Palma, M. A. Venneri, R. Galli, L. Sergi Sergi, L. S. Politi, M. Sampaolesi and L. Naldini: Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 3, 211-226 (2005)
doi:10.1016/j.ccr.2005.08.002
413 V. Fritz and C. Jorgensen: Mesenchymal stem cells: an emerging tool for cancer targeting and therapy. Curr Stem Cell Res Ther 3, 32-42 (2008)
doi:10.2174/157488808783489462
414 G. Chamberlain, J. Fox, B. Ashton and J. Middleton: Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25, 2739-2749 (2007)
doi:10.1634/stemcells.2007-0197
415 K. K. Hirschi and P. A. D'Amore: Pericytes in the microvasculature. Cardiovasc Res 32, 687-698 (1996)
doi:10.1016/0008-6363(96)00063-6
416 W. E. Thomas: Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev. 31, 42-57 (1999)
doi:10.1016/S0165-0173(99)00024-7
417 D. E. Sims: Diversity within pericytes. Clin Exp Pharmacol Physiol 27, 842-846. (2000)
doi:10.1046/j.1440-1681.2000.03343.x
418 U. Ozerdem and W. B. Stallcup: Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis;6, 241-249 (2003)
doi:10.1023/B:AGEN.0000021401.58039.a9
419 B. M. Seo, M. Miura, S. Gronthos, P. M. Bartold, S. Batouli, J. Brahim, M. Young, P. G. Robey, C. Y. Wang and S. Shi: Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364, 149-55 (2004)
doi:10.1016/S0140-6736(04)16627-0
420 A. Dellavalle, M. Sampaolesi, R. Tonlorenzi, E. Tagliafico, B. Sacchetti, L. Perani, A. Innocenzi, B. G. Galvez, G. Messina, R. Morosetti, S. Li, M. Belicchi, G. Peretti, J. S. Chamberlain, W. E. Wright, Y. Torrente, S. Ferrari, P. Bianco and G: Cossu: Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9, 255-267 (2007)
doi:10.1038/ncb1542
421 D. T. Covas, R. A. Panepucci, A. M. Fontes, W. A. Silva Jr, M. D. Orellana, M. C. Freitas, L. Neder, A. R. Santos, L. C. Peres, M. C. Jamur and M. A. Zago: Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146(+) perivascular cells and fibroblasts. Exp Hematol 36, 642-54. (2008)
doi:10.1016/j.exphem.2007.12.015
422 D. Shepro and N. M. Morel: Pericyte physiology. FASEB J. 7, 1031-1038 (1993)

423 G. Bergers and S. Song: The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7, 452-464 (2005)
doi:10.1215/S1152851705000232
424 E. H. Javazon, K. J. Beggs and A. W. Flake: Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32, 414-425. (2004)
doi:10.1016/j.exphem.2004.02.004

Key Words: Repair, Granulation Tissue, Stem Cells, Perivascular Niche, Pericyte, Atherosclerosis, Tumor Stroma, Review