[Frontiers in Bioscience S1, 477-491, June 1, 2009]
Integrins and extracellular matrices in pancreatic tissue engineering
Mansa Krishnamurthy1,2, Rennian Wang1,3,4
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TABLE OF CONTENTS
1. ABSTRACT
The role of integrin receptors in regulating numerous cellular programs have been well studied in the endocrine pancreas. These adhesion receptors and their interactions with the extracellular matrix (ECM) are important determinants of islet cell biology as they influence the development, survival and function of the islets of Langerhans. In this review, we will discuss the profound role of integrin-ECM relationships in controlling pancreatic tissue morphogenesis and the anti-apoptotic properties that these receptors confer through their dynamic and unique signaling pathways. Relationships between the ECM-integrin receptors will also be discussed in light of islet-based therapies including transplantation procedures and pancreatic tissue engineering initiatives.
2. INTRODUCTION
The cohesive nature of the islets of Langerhans, a highly specialized aggregate of cells, suggests that cell-cell and cell-matrix interactions are critical for survival, development and function of the endocrine pancreas. Although numerous receptors and cellular molecules have been shown to facilitate islet survival and function, of particular importance are the integrins. A superfamily of cell adhesion receptors which bind to the extracellular matrix (ECM), cell-surface and soluble ligands, integrins regulate a plethora of cellular programs including proliferation, migration, differentiation, survival and function (1-8).
In the field of islet biology, a large body of evidence supports the notion that interactions between the ECM and integrins provide a physical substratum for the spatial organization of cells and their downstream signaling pathways play critical roles in islet hormone regulation. Particular importance has been placed on the β1 subfamily of integrins, as they orchestrate the majority of islet cellular changes, and heavily influence alterations in hormonal gene expression (9,10). While possessing diverse ligand binding capabilities, the β1 integrin and its associated α subunits have repeatedly been shown to maintain islet architecture, by preventing anoikis and conferring a degree of stability (9,10,11).
The ability of integrins to coordinate events of cellular morphogenesis and regulate tissue homeostasis makes them ideal receptors to study and manipulate in islet biology, for greater remedial purposes such as islet transplantation and pancreatic tissue engineering. In this review, we focus on relationships between integrins and their respective ECM, which regulate processes of pancreatic morphogenesis, support islet viability, survival and function. Furthermore, we contend that the manipulation of these interactions may be beneficial in designing islet-based therapies including islet transplantation and the bioartificial endocrine pancreas, for the treatment of diabetes.
3. INTEGRINS AND EXTRACELLULAR MATRIX
3.1. Integrin family of receptors
Integrin transmembrane receptors are heterodimeric, composed of distinct α and β subunits. To date, 18α and 8β subunits have been identified, generating 24 distinct integrin receptors (1-4). The distinct structure of these heterodimers allows them to function as integrators of exterior and interior environments of a cell as they possess extracellular domains which bind to external ligands and cytoplasmic domains which facilitate interaction with the actin cytoskeleton and other affiliated proteins (1) (Figure 1). As a result, integrins exhibit unique and dynamic signaling capabilities, which allow them to coordinate and integrate extracellular events and intracellular changes (1,3,5,8). These bidirectional mechanisms described as "outside-in" and "inside-out" signaling, include the activation of numerous intracellular molecules which propagate conformational changes from cytoplasmic tails, across the membrane, toward ligand binding regions. This results in increased expression of integrins at the cell membrane as well as changes in receptor affinity and avidity which cause further alterations such as the redistribution of integrins and clustering, facilitating ECM binding (3,5).
Integrin receptors also demonstrate a considerable amount of overlap in their ligand binding specificities (1,8). The redundancy in integrin-ECM interactions suggests that specific receptor-matrix relations elicit highly specialized signaling functions and that a certain degree of compensation by other integrins or receptor types still allow for the development of normally functioning tissues. Recent developments of murine loss of function phenotypes in either constitutive or cell type-specific models have been especially important to our understanding of integrin/ECM signal transduction pathways which affect development and maintenance of tissues (6). These models display a wide range of phenotypes, from either early lethality to apparently normal mice, reinforcing the notion that hierarchies must exist among the integrin family of receptors, and that compensation between integrins or other receptor types allow for development of normally functioning tissues.
3.2. Extracellular matrix proteins (ECM)
Ligands of integrin receptors, the ECM, was initially viewed as a scaffold required for arranging cells within connective tissue, and providing physical support to tissues and organs. The ECM has now been redefined as a highly dynamic, compliable and flexible structure, capable of altering cell morphology, gene expression and tissue function (12,13).
ECM proteins are present in every tissue but are mostly concentrated in connective tissue and basement membranes (BM). A heterogenous mixture of water and polysaccharides as well as either collagens, proteoglycans, non-collagenous glycoproteins or elastins, the ECM organizes itself into a three-dimensional tissue-specific meshwork and constantly undergoes processes of remodeling controlled by ECM synthesis and degradation (12,13).
In addition to providing a physical framework for cells within a tissue, the ECM also influences cell function in two general ways. Firstly, ECM behaves as a storage site for multiple components including growth factors, cytokines, chemokines and enzymes and enables their mobilization and subsequently their interaction with specific receptor types on cell surfaces (12-15). Secondly, the ECM interacts with cellular receptors affecting cell adhesion and migration, triggering downstream signaling cascades which, in turn, regulate gene expression required for cell differentiation, proliferation and survival (12-15).
The wide spectrum of ECM proteins and their respective receptors makes way for great diversity for cell-matrix interactions. Moreover, the large variety of ECM composition contributes largely to the properties and function of each tissue and organ. Recent advances in knowledge about cell-ECM interactions have stimulated researchers to manipulate these relationships for organ regenerative purposes as well as tissue engineering.
3.3. Integrins/ECM and signaling transduction
Like the majority of cellular receptors, the activation of an integrin, mediated by adhesion, triggers downstream signaling cascades, by the induction of calcium fluxes, tyrosine and serine/threonine kinases and changes in RhoGTPases, which subsequently, cause changes in cell proliferation, differentiation and survival (5). The focal adhesion complex is a major group of proteins which undergoes activation as a result of cell adhesion through integrin receptors (16). Integrin-ECM interactions at focal contacts cause clustering of integrins and the recruitment of signaling molecules and actin filaments to the cytoplasmic domain of the receptor (5,8). These plaques are essential for integrins to establish connections to numerous signaling molecules including focal adhesion kinase (FAK), c-Src, phosphoinositide3-kinase (PI3-kinase), RhoGAP, paxillin, talin, p130CS, integrin-linked kinase and phosphorylated Caveolin-1 (17). It is now well known that integrin-mediated signals confer anti-apoptotic properties, via PI3-kinase and Akt signaling and stimulate cell cycle progression through extracellular signal-regulated kinase (ERK) and cyclinD1 activation (Figure 2) (18).
In addition to traditional signaling mechanisms, integrins can be also activated in the presence of soluble growth factors or ligands for other receptors, thereby influencing downstream cascades and mediating changes in cell survival and function. Since development of several tissues can proceed normally without the presence of widely expressed integrins, it is highly likely that these receptors participate in a much larger network of signaling processes. In fact, studies have demonstrated that cellular responses to soluble growth factors including EGF, PDGF, LPA and thrombin require the adhesion of cells on substrates via integrins (18-21). Furthermore, it is well known that the activation of parallel pathways by integrins and growth factors, synergize at the level of phosphorylation of downstream signaling proteins (5,19). The ECM, therefore, can be thought of as a niche which simultaneously provides a physical substratum and houses numerous growth factors, cytokines and mitogenic signals, allowing for integrins to influence numerous cellular behaviours including survival and function.
4. INTEGRINS AND ECM IN ISLET FORMATION
ECM proteins and cell adhesion receptors have been well known to contribute to the organogenesis, morphogenesis and cytodifferentiation of several organ systems including the pancreas (22). Recent findings have demonstrated that integrin adhesion systems are implicated in numerous developmental stages and regulate diverse processes including cell positioning, tissue patterning, compartmentalization and cell polarity (22-26).
In the pancreas, many integrin-ECM interactions have been characterized in rodent and human systems as summarized in Tables 1 and 2. The migration of islet precursors from the ductal epithelium into the surrounding mesenchyme is governed by the activities of matrix metalloproteinases (MMPs) (Figure 3) (27). In fact, interactions between MMP2 and MMP9 and their inhibitors, tissue inhibitors of MPs (TIMPs), are largely responsible for processes of aggregation. Transforming growth factor-β (TGF-β) signaling also stimulates islet morphogenesis by enhancing MMP2 expression and activity, further supporting the role of MMPs in islet cell morphology and development (27,28). Epidermal growth factor receptor (EGFR) signaling acts as a positive regulator of MMP activity; EGFR mutant mice display a decrease in pancreas size due to reduced epithelial branching and islet migration (29). Thus, matrix degradation is critical for remodeling, epithelial morphogenesis and migration of endocrine precursors.
Studies have identified the BM, rich in laminin, as a critical mediator of ductal and tubular morphogenesis and differentiation, giving rise to either endocrine or exocrine precursors (Figure 3). The epithelial-mesenchymal interface, established by the BM, is rich in biologically active components including collagens, heparin and chondroitin sulfate, laminin and fibronectin (30-36). Specifically, the role of laminin in the regulation of ductal morphogenesis from undifferentiated pancreatic epithelium has been well investigated (30,37-39). Organization and concentration of laminin-1 in the BM is critical for its development and subsequent influence over epithelial cell differentiation into either the endocrine or exocrine pancreas. Direct contact of pancreatic epithelium with laminin-1 allows for the formation of the exocrine pancreas, whereas those cells which are not involved in this interaction organize into endocrine cell clusters and eventually form islets by the end of gestation (30). Highly specialized experimental models in the rodent, where early pancreatic epithelium is grown under laminin-poor renal capsules, resulted in the default selection of the endocrine lineage, demonstrating that the absence of laminin is necessary for endocrine cell formation (30). In vitro experiments have further solidified the notion that interactions between laminin-1 and integrin receptors allow for epithelial cell differentiation.
The ECM also confers migratory properties essential for islet formation. Endocrine precursors located in pancreatic ducts, migrate through the basement membrane and cluster with the aid of integrin receptors during early stages of islet assembly (Figure 3) (40,41). Studies by Cirulli and colleagues have demonstrated that integrins αvβ3 and αvβ5 contribute to the migration of putative endocrine progenitor cells (42). The treatment of human fetal islet-like clusters with anti-αvβ3 and anti-αvβ5 antibodies resulted in the detachment of cells and three-dimensional clustering. Furthermore, when human fetal pancreatic fragments were transplanted into the kidney capsule of NOD/SCID mice along with RGD blocking peptides, a significant disruption in islet architecture and size was observed (42).
Another migratory cue which regulates islet cell development is netrin (43). A well known contributor of axon guidance, netrin is expressed in discrete pancreatic populations within fetal and adult ductal epithelia and exocrine tissue. Although it is not found in adult islets, it is localized to the basal surfaces of pancreatic cells. Integrins α6β4 and α3β1 (43) mediate the adhesion and migration of fetal pancreatic epithelial cells to netrin-1. The majority of cells which migrate on netrin-1 are Pdx-1+, suggesting that netrin-1 supports the migration of pancreatic progenitors (43).
Once islets form, islet-ECM and cell-cell interactions become essential for proper coordination of events including development and maturation. Vitronectin and its association with several integrin receptors have been shown to contribute significantly to human fetal islet development. Its association with epithelial and insulin+ cells combined with its restricted expression near progenitor populations, suggests that its synthesis and deposition is involved in the regulation of morphogenetic events needed for islet neogenesis (42). Moreover, in vitro experiments have identified relationships between vitronectin and integrins αvβ1 and αvβ5 as important mediators of human beta cell adhesion, spreading and motility (42). In particular, αvβ1 was responsible for migration of human fetal beta cells. The developmental loss of this integrin in adult beta cells resulted in the lack of migration, suggesting that this receptor is critical for motile processes required for fetal islet assembly. Given that expression of the αvβ1 integrin is lost in adult beta cells, it is most likely that this receptor aids in static cell-matrix interactions (42).
Numerous other studies have also demonstrated the importance of the β1 integrin in processes of remodeling and maturation (9,10,44). The spatial and temporal expression of the β1 integrin and its associated α subunits has been studied in the fetal and pre- and post-natal rat pancreas, indicating the importance of the β1 integrin family during development and suggesting that these heterodimers contribute substantially to islet restructuring (9). The β1 integrin was expressed in ductal populations as well as glucagon+ and insulin+ cell types in the rat pancreas (9). While expression levels of integrin α3β1 and α6β1 significantly increase early in development, α5β1 remains constant. The expression of these integrins decrease as rat pancreatic development progresses, possibly since the majority of pancreatic construction occurs by e18 with remodeling occurring until the first three weeks of postnatal life.
Similarly, in the human fetal pancreas, the importance of α3β1, α5β1 and α6β1 has been demonstrated, as these integrins exhibit specific expression patterns during progressive pancreatic development (10). Although the expression of all three integrin heterodimers was noted before the budding of glucagon+ and insulin+ cells from pancreatic ducts, α3β1 and α6β1 demonstrated significant increases in expression by 16-20 weeks of development. These studies suggest that the formation and maturation of the islets of Langerhans requires increasing α3β1, a 5b 1 and α6β1 expression to contribute adhesive and migratory properties (10).
Collagen IV and its interactions with integrin α1β1 has also been shown to support the adhesion and migration of human fetal and adult beta cells (45). The migratory response of fetal beta cells was much higher in comparison with adult beta cells, suggesting that this critical basement membrane protein provides the necessary motile processes required for islet neogenesis. The strong adhesion rate and maturational loss of migration, proposes that collagen IV is essential for maintenance of architecture and integrity in adult islets.
Co-localization studies of these integrins with specific ECM proteins have further solidified the importance of integrin-ECM relationships in the development of the islets of Langerhans. Association of collagen IV, laminin and fibronectin with the β1 integrin family further reinforces that the multiplicity of this receptor is critical for islet development and biology (9,10).
Lastly, cell adhesion molecules (CAMs) and cadherins have also been shown to contribute to proper islet formation and maintenance of architecture (46,47). Cadherins E and N are expressed in areas of cell contact between beta cells and other cell types (46,47), while R-cadherin is prominently expressed only on beta cells (46,47). Neural cell adhesion molecule (N-CAM) is expressed on both beta cells and other cell types in the pancreas and is required for proper islet cell aggregation and organization into typical islet structures, with beta cells concentrated in the center and alpha cells remaining in the periphery (47,48).
5. INTEGRINS AND ECM IN ISLET SURVIVAL AND FUNCTION
Several studies have implicated integrin-matrix relationships as critical determinants of islet survival, proliferation, differentiation and function. Given that the ECM confers stability and support to islets, destruction of matrix proteins would undoubtedly increase cell necrosis and apoptosis. In fact, freshly isolated canine islets were shown to undergo apoptosis, due to loss of the perinsular-basement membrane (49). However, when cultured in or on matrix proteins such as collagen I and fibronectin, these islets exhibited improved survival. These islets were also shown to undergo a transdifferentiation process, characterized by a switch from islet to ductal phenotype indicating a loss in stability, as a result of perturbed islet-matrix relationships (50). Moreover, the aggregatory nature of pancreatic islets also contributes to the survival of individual islet cells. Cell sorting experiments, whereby human islets are dispersed into single cells resulted in reduced survival and increased apoptosis (51). However, matching ECM proteins to specific integrin receptors expressed on islet cells improved cell survival.
Perturbation studies using immunoneutralizing antibodies or siRNA have been valuable for the identification of key integrin receptors which mediate adhesion, spreading and proliferation when interacting with specific matrix proteins. Again, recent evidence has highlighted the importance of the β1 integrin family and its associated α subunits in the regulation of numerous islet cell activities. Both primary and transformed rat islet cells were shown to form aggregates resembling native islets when cultured on collagen I, in vitro (52). Interactions between matrices and the β1 integrin were further solidified when a decrease in adhesion and spreading were observed upon treatment of rat islet cells with anti-β1 integrin, and subsequently cultured on bovine corneal endothelial cell extracellular matrix (BCEM) (53). Isolated rat islets and human fetal islet epithelial clusters demonstrated similar decreases in adhesion and spreading when cultured on fibronectin, laminin and collagen I after treatment with an immunoneutralizing antibody for β1 (9,10). Blocking the β1 integrin resulted in increased apoptosis of beta cells in rat and human fetal primary cells, and reduced Pdx-1, insulin and glucagon gene expression. Taken together, these studies indicate the importance of the β1 integrin in mediating cellular function and conferring anti-apoptotic properties.
Relationships between α6β1 and 804G matrix (secreted by 804G epithelial cells) have also been shown to affect beta cell function in vitro. The increased insulin secretory response noted when rat beta cells adhered to this matrix was shown to be mediated through the α6β1 integrin (54). Furthermore, adhesion of cells to this matrix and treatment with insulin secretagogues allowed for increased expression of the integrin itself, suggesting that both "inside-out" and "outside-in" signaling mechanisms are active and critical for islet function. Laminin, the primary constituent of the 804G matrix, is thought to be responsible for the majority of positive effects on islet survival and function (55). Both beta cell spreading and insulin secretion in response to glucose stimulation, on 804G matrix, was significantly inhibited when cells were treated with anti-laminin-5 antibody and complementary results were noted with anti-β1 integrin treatments.
The above studies clearly demonstrate that integrin-matrix interactions are critical for the viability and function of islets, and that in most cases "inside-out" and "outside-in" signaling mechanisms are necessary for facilitating these events. Studies exploring changes in downstream signaling cascades have primarily identified FAK, MAPK and ERK-activation as critical mediators of islet cellular events (11,44,56). A decrease in insulin content and subsequent increase in insulin release as a result of human fetal beta cell adhesion to collagen IV and vitronectin was shown to be dependent on ERK signaling (57). Collagen IV was also shown to induce ERK-dependent insulin secretion in human adult beta cells (57). Moreover, laminin-5 and β1 interactions increased FAK and ERK1/2 phosphorylation (11). Metabolic changes triggering the release of intracellular calcium are also suspected to be involved in the functional changes noted in integrin-matrix interactions.
While the influential role of the β1 integrin in islet survival and function has been well established, information regarding the contributions of its associated α subunits is limited. Several studies have demonstrated high expression levels of integrins α3, α5 and α6 in islet cell populations in both rodent and human systems (9,10,53) - but their regulation of islet survival and function and their downstream signaling cascades has not been extensively studied. Recent evidence has shown that interactions between collagen I/IV and the α3 integrin is important for maintenance of viability along with Pdx-1 and insulin expression in both the INS-1 and primary human fetal islet cells (56). Moreover, perturbing the function of the α3 integrin resulted in decreases in FAK, AKT and ERK1/2 phosphorylation (Figure 2). These findings highlight: (i) that α integrin subunits also modulate islet cell survival and function and (ii) that they are capable of signaling through highly specialized downstream cascades, independent of the β1 integrin. The majority of integrin-matrix interactions have been shown to potentiate islet survival and function; however, it is important to note that a loss in function can be caused by adhesion to certain ECM substrates. Human fetal and adult beta cells demonstrated significant decreases in insulin gene expression when cultured on collagen IV and vitronectin (57). Similarly, blockade of the β1 integrin in isolated rat islets, reduced cellular apoptosis and increased Akt phosphorylation (58).
6. ISLET TRANSPLANTATION
Diabetes mellitus, a metabolic disorder of either absolute or relative insulin deficiency, affects 194 million people today (59). Although exogenous insulin therapy is currently the most common form of treatment, normal physiological glycemic control can only be achieved by beta cell replacement. There are several advantages to islet transplantation, including a simple administration route which is minimally invasive and the possibility of repeating transplantation procedures without major patient discomfort (60). The Edmonton protocol, was initially successful, allowing for 80% insulin independence for one year (59,61). However, long-term function of islet grafts failed with less than 10% of patients maintaining insulin independence for 5 years (60). The possible reasons for poor long-term graft survival may include excessive cell death due to isolation, inadequate immunosuppression and beta cell toxicity resulting in the loss of long-term viability and islet mass (62) as well as limited islet supply, which also contribute to the current limitations of islet transplantation. Recent research has shown that certain immunosuppressive treatments greatly affect the long-term survival of islet grafts by inhibiting the natural process of neogenesis and negatively impacting beta cell survival, proliferation and differentiation (63). Although there are several issues which still need to be addressed through clinical and basic science research, there has been immense progress in the field of islet transplantation.
6.1. Integrin-ECM interactions protect b -cell function following transplantation
The in vitro generation and expansion of islets with maintenance of viability and function is a possible alternative that can circumvent donor shortage limitations (64,65). Several expansion programs worldwide are currently investigating mechanisms of beta cell growth, by focusing on either beta cell neogenesis or replication (66-76). In this regard, the culture of islets on substrates which mimic natural microenvironments seems to be a logical prospect. Islet-ECM interactions have been shown to inhibit apoptosis and induce prolonged survival of beta cells after isolation (44,49). These interactions also allow for extensive manipulation for successful in vitro survival and proliferation.
A study by Bonner-Weir et al. (69) examined the proliferation and differentiation of human ductal tissue into islet cells on Matrigel, as well as their function in vitro. Findings of this study highlight two key areas of research: (i) matrix proteins have the ability to support and stimulate three dimensional organization of pancreatic precursors into islet cells, which in turn, facilitates survival and function and (ii) that the shortage in donor material can be alleviated by inducing ductal precursors to differentiate into an islet population through three dimensional assays. Long-term culture studies of human islets embedded in type I collagen maintained their architecture and high secretory capacities (77). Moreover, culturing isolated rat islets on a collagen I, II, IV and laminin hydrogel resulted in significant decreases in cell death, but no changes in insulin, glucagon and somatostatin expression were observed (78). A study by Montessano et al. (52) demonstrated the ability of dispersed neonatal rat islet cells to reorganize into islet-like organoids within a three dimensional collagen matrix (52). Islet cells seeded on collagen matrix remained in monolayer, while the addition of a second layer of collagen I resulted in a dramatic reorganization of islets. The typical architecture of islets in vivo, was re-established in this three dimensional model, as beta cells remained concentrated in the center of these organoids and alpha and delta cells were located in the periphery.
A relatively novel and interesting area of research is focused on using naturally occurring matrices (Table 2) to culture and induce the expansion of islets. The small intestinal submucosa (SIS), a cell-free matrix extracted from porcine intestines, is rich in collagens, glycoproteins, proteoglycans and glycosamineglycans (79,80). Its use as a scaffold in the remodeling and regeneration of a variety of other tissues suggests that it may be useful in potentiating islet survival and function. The in vitro tissue culture of isolated rat islets on SIS resulted in the maintenance of morphology, increased insulin secretion upon glucose challenge and a significant reduction in cell death, suggesting that the SIS confers both protection and support to islets (79-82). Moreover, intrinsic mechanical properties make this matrix highly compliable and histocompatible while its porous nature allows for the diffusion of cellular nutrients.
Recent islet isolation methods have significantly improved over the last three decades; however the current method of collagenase digestion still destroys the basement membrane which results in reduced islet viability and function (81). In order to improve current transplantation methods, an understanding of the peri-insular membrane, islet-exocrine interface and general distribution of matrix proteins in the islet and surrounding periphery is required.
6.2. Islet transplantation: important points of consideration
Expression patterns of the laminin, fibronectin and collagen family of proteins have been thoroughly examined in both human and rodent pancreas. Collagens I, IV and V are abundantly expressed in the peri-insular region of the human pancreas, while collagen V and VI expression is significant around adult islets (83). Moreover, collagen VI demonstrated consistent levels of expression in the islet-exocrine interface throughout the head, body and tail regions of the pancreas (84). Laminin was found to be expressed in acinar basement membrane and the surrounding ductal epithelium but no significant expression was found surrounding adult murine islets (85,86). Interestingly, fibronectin expression was predominant underneath endothelial cells, in the perivascular regions, the islet periphery and intraglobular regions (42,86). The less studied proteoglycan, Lumican, was found to be localized in alpha cells (87). The corresponding integrin receptors reportedly expressed in islets include α3, α5, αV and β1 (88). In fact, β1, α2 and α6 were found in the parenchyma, whereas α3 was expressed in ductal cells. The laminin receptor α6 demonstrated high levels of expression in exocrine acini, while the expression of fibronectin receptors, α4 and α5, was primarily noted in the ECM surrounding ducts and vessels (88). After islet isolation, the disruption of islet-matrix relationships results in decreased integrin expression which may be due to perturbation of the peri-insular basement membrane. This critical information, provided by immunohistology studies of matrix and integrin expression, should be taken into consideration during islet isolation, and methods of preserving such relationships should be devised.
A recent finding by Nikolova et al. (89) demonstrated that β cells rely on adjacent capillary endothelial cells to produce basement membrane ECM proteins. As a result, a depletion of islet capillaries demonstrated lower levels of insulin gene expression and secretory granules (89). Developmental studies also showed that a rich vasculature is necessary for the induction of insulin in embryos, indicating that the ECM is involved in ensuring intact β cell function (90,91). In vitro assays conducted with several varieties of laminin demonstrated up to 2 fold increases in insulin gene expression. These results indicate that the existing dynamic between endothelial and hormone producing cells, which reside within the islet, must also be preserved in order to ensure success of islet transplantation procedures.
7. BIOARTIFICAL ENDOCRINE PANCREASS: PROBLEMS, PROMISE AND PROGRESS
The extensive research examining islet-matrix interactions lends itself to future therapies involving the derivation and use of encapsulated islets referred to as the bioartifical endocrine pancreas (BAP). The construct of this potential therapy requires the fulfillment of specific criteria including biocompatibility, adequate diffusional properties and easy retrievability (92-94). Moreover, the device must facilitate the maintenance of functional islets, which are typically embedded in either a biological or synthetic matrix and encapsulated within a semipermeable membrane, permitting the exchange of nutrients, glucose and insulin (94). An ideal therapy, the concept of the BAP makes possible the use of non-human donors, reducing limitations associated with tissue shortage. More importantly, the BAP is designed to by-pass natural immune reactions of the body, so that immunosuppressive therapies are not required.
The implantation of these devices may be into the blood supply or peritoneal cavity and are meant to mimic the behavior and function of a healthy pancreas (92-94). Designing a BAP is a very delicate procedure, as islets must be enveloped with homogenous and semi-permeable artificial membranes, without disruption of tissue morphology, integrity or functional competence. The BAP is an ideal device for the treatment of type I diabetes, but effectively controlling biomaterial and functional aspects has proven difficult in the development of an effective prototype. Nevertheless, several industrial and basic science laboratories are dedicated to developing the BAP into a plausible therapy for patients with insulin-dependent diabetes. There are three different encapsulated systems currently being used: (i) intravascular macrocapsules - perfusions chambers connected to the blood circulation, (ii) extravascular macrocapsules - diffusion chambers that are transplanted intraperitoneally or subcutaneously or (iii) extravascular microcapsules - encapsulation of one or few islets in a membrane (92,93,95). While all three prototypes have been investigated, the extravascular microcapsules have been studied at large.
7.1. Encapsulation: enhancing islet cell survival and function
It has been demonstrated by several research groups that the efficient function of islet cell types in the BAP is dependent on an effective matrix structure, either synthetic or biological. While the majority of studies have made use of synthetic matrix constituents, a few laboratories have reported the benefits of embedding islets in biologically active compounds, thus taking advantage of integrin-ECM interactions. A recent study by Edamura et al. (96) compared the effects of embedding isolated porcine islets in either Matrigel or type I collagen. The Matrigel prototype stimulated a greater increase in insulin production and efficiently reduced blood glucose levels when implanted, in comparison with the collagen I capsule, indicating that specific biological compounds are more suitable for the derivation of a BAP prototype (96). Another study was conducted by Salvay et al. (97), where streptozotocin-induced diabetic mice were implanted with microporous polymer scaffolds adsorbed with collagen IV, fibronectin, laminin-332 or serum proteins, containing 125 mouse islets. Mice which received the collagen IV-adsorbed graft, achieved euglycemia the fastest and their response to glucose challenge was comparable to normal mice (97). Fibronectin and laminin grafts also promoted euglycemia, but required more time (97). Finally, all three ECM protein grafts displayed normal cell-cell contact and intact islet architecture as well as increased vessel density within the graft when compared to serum-coated scaffolds, indicating that the incorporation of ECM proteins into a BAP prototype enhances long-term islet cell survival and function (97).
Seeding of islet cells into microporous scaffolds has also been shown to enhance the survival of implanted grafts and reverse diabetes in streptozotocin-induced diabetic mice (98). These microporous scaffolds possess a high surface area/volume ratio supporting cell adhesion, and increase nutrient transport by diffusion from neighbouring tissue. These scaffolds also allow for cell infiltration from surrounding tissue, thus enabling the full integration of the graft into the host which is especially important for re-establishment of the vascular network within the prototype. Blomeier et al. (98) demonstrated richly vascularized islets in microporous scaffolds two weeks following their implantation. These islets highly expressed endocrine cell markers insulin, Pdx-1 and somatostatin (98). Finally, the implanted microporous scaffolds were able to achieve euglycemia in diabetic mice, indicating that this prototype enables the survival of islets and increases function (98).
Exposing isolated islets to a combination of biological and synthetic peptides is also advantageous. The addition of laminin peptides to a poly (ethylene glycol) capsule, preserved viability, reduced apoptosis and enhanced insulin secretion from MIN6 cells. Moreover, specific laminin sequences were able to further enhance the survival and function of these cells, indicating that the inclusion of specific peptides may also be useful when designing a BAP (99).
7.2. Encapsulation: the disadvantages
Although the studies described above demonstrate promising results, the long-term survival and function of islets following encapsulation is limited. The factors which impede the success of encapsulation for islet transplantation include: (i) biocompatibility, (ii) inadequate immunoprotection and (iii) hypoxia.
Inadequate biocompatibility is identified by pericapsular overgrowth on microcapsules that consist of fibroblasts and macrophages. Studies by Safely et al. (100) demonstrated inflammatory cell deposition around microencapsulated porcine islet xenografts in NOD mice 15 days following transplantation and that tissue overgrowth on the microcapsules is directly related to islet graft failure (100). Causes of this fibrotic growth include the biomaterials used to fabricate the BAP, as well as imperfect encapsulation. The search for materials with better diffusional properties and minimal cellular overgrowth has led to the consideration of mainly synthetic compounds (92,101,102), however research examining the biocompatibility of natural matrices is currently underway. The surface textures of BAP devices have also been shown to impact fibrotic and immune responses.
Although islets are protected from cellular engulfment in a BAP, they still remain permeable to small molecules of the immune system including NO, oxygen radicals, and inflammatory cytokines including IL-1β, TNF-α and IFN-γ from macrophages and T-cells involved in the inflammatory reaction (92,93,103-105). The use of specialized synthetic materials including polyetheretherketone (PEEK) for membranes, as well as pre-coating procedures with proteins has demonstrated a certain level of protection from cytokines including IL-1, while maintaining adequate insulin secretion upon glucose stimulation (92). Although a few studies show improvement to a certain extent, small immune molecules still destroy islets, leading to poor functioning of grafts.
Lastly, cell death as a result of hypoxia is another disadvantage of encapsulation. The islet isolation process destroys both intra-islet blood vessels and the surrounding supply, but a new vasculature can be established during the first few weeks of transplantation. Unfortunately, the presence of a barrier membrane prevents the formation of blood vessels in and around the islets, preventing revascularization of the isolated tissue (92). Consequently, tissue oxygen and nutrient requirements are not met and the metabolite removal process is greatly hindered, leading to hypoxic cell death of the core tissue (93). To circumvent hypoxia and its consequences, implanting a BAP into areas with high levels of vascular perfusion, has been examined by Knight et al. Islets were seeded into vascular chambers near the splenic or epigastric artery or vein, and allowed for normoglycemia by 7 weeks post-implantation (105). Although these results are encouraging, the implantation of a BAP near a vascular bed poses other threats including embolism and thrombogenesis, and thus may not be the best option. Several other approaches have been proposed to overcome oxygen transport limitations including the incorporation of oxygen carriers/transporters such as hemoglobin (106,107), as well as oxygen generator systems which electrolyze water to form oxygen and hydrogen within a BAP prototype (108). Finally, several laboratories have been dedicated to exploring mechanisms of neovascularization into potential implantation sites for the BAP, prior to transplantation of the graft, as a strategy to overcome hypoxia.
8. 3D-SCAFFOLDS
A relatively novel area of research within the encapsulation field is examining the differentiation of embryonic stem cells (ESC) within 3D scaffolds. A recent study by Lees et al. (108) examined the differentiation potential of hESCs following their encapsulation and implantation in between liver lobules of SCID mice. Interestingly, specific markers of the endoderm and pancreas were detected including GLP-1, IAPP and insulin (110). Moreover, a significant deposition of matrices laminin and collagens I and IV were observed within the capsule, along with endothelial progenitor cells, indicating the formation of a primitive pancreas-like structure (109). Similarly, encapsulated islet-like cell clusters isolated from fetal pigs underwent differentiation into viable and functional islets which normalized blood glucose levels in diabetic mice (110). These results indicate the potential use of progenitor cells in 3D scaffolds as a plausible prototype for the BAP.
9. SUMMARY AND PERSPECTIVES
Manipulation of ECM-integrin interactions is an attractive strategy for potentiating beta cell survival and function in either islet transplantation or the bio-artificial pancreas. Several research groups have reported that these relationships are beneficial for survival, proliferation and function of islet cells in vitro, by enhancing either neogenesis or replication. Unfortunately, the benefits of these relationships have not been shown to translate well into therapeutic approaches such as islet transplantation or the bio-artificial endocrine pancreas. The majority of challenges are associated with long-term survival and function of islets. Further studies are required to fully understand integrin-ECM interactions and apply this knowledge to create clinically-effective methods for diabetes treatment.
10. ACKNOWLEDGEMENTS
This work was supported by grants from the Natural Sciences & Engineering Research Council of Canada. Dr. Wang is supported by a New Investigator Award from Canadian Institutes of Health Research.
11. REFERENCES
1. N. J. Boudreau & P. L. Jones: Extracellular matrix and integrin signalling: the shape of things to come. Biochem J 339, 481-488 (1999)
doi:10.1042/0264-6021:3390481
PMid:10215583 PMCid:1220180
2. R. L. Juliano, P. Reddig, S. Alahari, M. Edin, A. Howe & A. Aplin: Integrin regulation of cell signalling and motility. Biochem Soc Transactions 32(3), 443-446 (2004)
doi:10.1042/BST0320443
PMid:15157156
3. M. G. Coppolino & S. Dedhar: Bi-directional signal transduction by integrin receptors. Int Journal of Biochem and Cell Bio 32, 171-188 (1999)
doi:10.1016/S1357-2725(99)00043-6
4. C. F. French-Constant & H. Colognato: Integrins: Versatile integrators of extracellular signals. Trends in Cell Bio 14(12), 678-695 (2004)
doi:10.1016/j.tcb.2004.10.005
PMid:15564044
5. E. H. J. Danen & A. Sonnenberg: Integrins in regulation of tissue development and function. Journal of Pathology 200, 471-480 (2003)
doi:10.1002/path.1416
PMid:12845614
6. D. Bouvard, C. Brakebusch, E. Gustafsson, A. Aszodi, T. Bengtsson, A. Bern & R. Fassler: Functional consequences of integrin gene mutations in mice. Circ Res 89,211-223 (2001)
doi:10.1161/hh1501.094874
PMid:11485971
7. C. Brakebusch & R. Fassler: β1 integrin function in vivo: Adhesion, migration and more. Cancer and Metastasis Reviews 24, 403-411 (2005)
doi:10.1007/s10555-005-5132-5
PMid:16258728
8. J. W. Lee & R. Juliano: Mitogenic Signal Transduction by Integrin- and Growth Factor receptor-mediated pathways. Molecules and Cells 17(2), 188-202 (2004)
9. N. K. Yashpal, J. Li, M. B. Wheeler & R. Wang: Expression of β1 Integrin Receptors during Rat Pancreas Development - Sites and Dynamics. Endocrinology 146(4), 1798-1807 (2005)
doi:10.1210/en.2004-1292
PMid:15618357
10. R. Wang, J. Li, K. Lyte, N. K. Yashpal, F. Fellows & C. Goodyear: Role of β1 integrin and its associated α3, α5 and α6 subunits in the development of the human fetal pancreas. Diabetes 54, 2080-2089 (2005)
doi:10.2337/diabetes.54.7.2080
PMid:15983209
11. E. Hammar, G. Parnaud, D. Bosco, N. Perriraz, K. Maedler, M. Donath, G. Rouiller & P. Halban: Extracellular matrix protects pancreatic β-cells against apoptosis: role of short- and long-term signaling pathways. Diabetes 53, 2034-2041 (2004)
doi:10.2337/diabetes.53.8.2034
PMid:15277383
12. A. Aszodi, K. R. Legate, I. Nakchbandi & R. Fassler: What Mouse Mutants Teach Us About Extracellular Matrix Function. Annu Rev Cell Dev Biol 22, 591-621 (2006)
doi:10.1146/annurev.cellbio.22.010305.104258
PMid:16824013
13. C. Streuli: Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol 11, 634-640 (1999)
doi:10.1016/S0955-0674(99)00026-5
PMid:10508658
14. F. Rosso, A. Giordano, M. Barbarisi & A. Barbarisi: From Cell-ECM Interactions to Tissue Engineering. J Cell Physiol 199, 174-180 (2004)
doi:10.1002/jcp.10471
PMid:15039999
15. H. K. Kleinman, D. Philp & M. P. Hoffman: Role of the extracellular matrix in morphogenesis. Curr Opin Cell Biotech 14, 526-532 (2003)
doi:10.1016/j.copbio.2003.08.002
PMid:14580584
16. M. Schaller, C. Borgman, B. S. Cobb, R. R. Vines, A. B. Reynolds & J. T. Parsons: pp125FAK, a structurally distinctive protein-kinase associated with focal adhesions. Proc Natl Acad Sci USA 89, 5192-5196 (1992)
doi:10.1073/pnas.89.11.5192
17. S. M. Schoenwaelder & K. Burridge: Bidirectional signaling between the cytoskeleton and integrins. Curr Opin Cell Biol 11, 274-286 (1999)
doi:10.1016/S0955-0674(99)80037-4
PMid:10209151
18. R. O. Hynes: Integrins: Bidirectional, allosteric signaling machines. Cell 110, 673-687 (2002)
doi:10.1016/S0092-8674(02)00971-6
PMid:12297042
19. M. A. Schwartz & M. H. Ginsberg: Network and crosstalk: integrin signaling spreads. Nature Cell Biol 4, E65-68 (2002)
doi:10.1038/ncb0402-e65
PMid:11944032
20. K. M. Yamada & S. Even-Ram: Integrin regulation of growth factor receptors. Nature Cell Biol 4, E75-76 (2002)
doi:10.1038/ncb0402-e75
PMid:11944037
21. B. P. Elicieri: Integrin and growth factor receptor crosstalk. Circ Res 89, 1104-1110 (2001)
doi:10.1161/hh2401.101084
PMid:11739274
22. J. P. Thiery: Cell adhesion in development: a complex signaling network. Curr Opin Gen and Develop 13, 365-371 (2003)
doi:10.1016/S0959-437X(03)00088-1
23. R. O. Hynes: Cell-matrix adhesion in vascular development. J Thromb Haemost 5 (Suppl 1), 32-40 (2007)
doi:10.1111/j.1538-7836.2007.02569.x
PMid:17635706
24. R. O. Hynes: The emergence of integrins: a personal and historical perspective. Matrix Biol 23, 333-340 (2004)
doi:10.1016/j.matbio.2004.08.001
PMid:15533754
25. R.O. Hynes & Q. Zhao, Q: The evolution of cell adhesion. J Cell Biol 150, F89-F95 (2000)
doi:10.1083/jcb.150.2.F89
26. P. C. Marchisio: Integrins and tissue organization. Adv Neuroimmunol 3, 214-234 (2007)
27. F. Miralles, T. Battelino, P. Czernichow & R. Scharfmann: TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol 143, 827-836 (1998)
doi:10.1083/jcb.143.3.827
PMid:9813100 PMCid:2148155
28. S. G. Rane, J. Lee & H. Lin H: Transforming growth factor-β: Role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev 17, 107-119 (2005)
doi:10.1016/j.cytogfr.2005.09.003
29. P. J. Miettinen, M. Huotari, T. Koivisto, J. Ustinov, J. Palgi, J. Rasilainen, E. Lehtonen, E. Keski-Oja & T. Otonkoski: Impaired Migration and Delayed Differentiation of Pancreatic Islet Cells in Mice Lacking EGF-Receptors. Development 127, 2617-2627 (2000)
30. C. A. Crisera, A. S. Kadison, G. D. Breslow, T. S. Maldonado, M. T. Longaker & G. K. Gittes: Expression and role of laminin-1 in mouse pancreatic organogenesis. Diabetes 49, 936-944 (2000)
doi:10.2337/diabetes.49.6.936
PMid:10866045
31. I. Virtanen, D. Gullberg, J. Rissanen, E.Kivilaakso, T. Kiviluoto, L. A. Laitinen, V. P. Lehto & P. Ekblom: Laminin α1 chain shows a restricted distribution in epithelial basement membranes of fetal and adult human tissues. Exp Cell Res 257, 298-309 (2000)
doi:10.1006/excr.2000.4883
PMid:10837144
32. I. Virtanen, M. Banerjee, J. Palgi, O. Korsgren, A. Lukinius, L. E. Thornell, Y. Kikkawa, K. Sekiguchi, M. Hukkanen, Y. T. Konttinen & T. Otonkoski: Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia 51, 1181-1191 (2008)
doi:10.1007/s00125-008-0997-9
PMid:18438639
33. H. Colognato & P. D. Yurchenco: Form and function: the laminin family of heterotrimers. Dev Dyn 218, 213-234 (2000)
doi:10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R
PMid:10842354
34. K. Kuhn: Basement membrane (type IV) collagen. Matrix Biol 14, 439-445 (1995)
doi:10.1016/0945-053X(95)90001-2
PMid:7795882
35. J. C. Myers, A. S. Dion, V. Abraham & P. S. Amenta: Type XV collagen exhibits a widespread distribution in human tissues but a distinct localization in basement membrane zones. Cell Tissue Res 286, 493-505 (1996)
doi:10.1007/s004410050719
PMid:8929352
36. O. Musso, M. Rehn, J. Saarela, N. Theret, J. Lietard, J. Hintikka, D. Lotrian, J. P. Campion, T. Pihlajaniemi & B. Clement: Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver. Hepatology 28, 98-107 (1998)
doi:10.1002/hep.510280115
PMid:9657102
37. G. K. Gittes, P. E. Galante, D. Hanahan, W. J. Rutter & H. T. Debase: Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors. Development 122, 439-447 (1996)
38. T. S. Maldonado, C. A. Crisera, A. S. Kadison, S. L. Alkasab, M. T. Longaker & G. K. Gittes: Basement Membrane Exposure Defines a Critical Window of Competence for Pancreatic Duct Differentiation from Undifferentiated Pancreatic Precursor Cells. Pancreas 21, 93-96 (2000)
doi:10.1097/00006676-200007000-00057
PMid:10881938
39. A. S. Kadison, T. S. Maldonado, C. A. Crisera, M. T. Longaker & G. K. Gittes: In Vitro Validation of Duct Differentiation in Developing Embryonic Mouse Pancreas. J Surg Res 90, 126-130 (2000)
doi:10.1006/jsre.2000.5876
PMid:10792952
40. S. K. Kim & M. Hebrok: Intercellular signals regulating pancreas development and function. Genes Dev 15, 111-127 (2001)
doi:10.1101/gad.859401
41. S. E. Perez, D. A. Cano, T. Dao-Pick, J. P. Rougier, Z. Werb & M. Hebrok: Matrix Metalloproteinases 2 and 9 Are Dispensable for Pancreatic Islet Formation and Function In Vivo. Diabetes 54, 694-701 (2005)
doi:10.2337/diabetes.54.3.694
PMid:15734845
42. V. Cirulli, G. M. Beattie, G. Klier, M. Ellisman, C. Ricordi, V. Quaranta, F. Frasier, J. K. Ishii, A. Hayek & D. R. Salomon: Expression and Function of αvb3 and αvb5 Integrins in the Developing Pancreas: Roles in the Adhesion and Migration of Putative Endocrine Progenitor Cells. J Cell Biol, 150(6), 1445-1449 (2000)
doi:10.1083/jcb.150.6.1445
PMid:10995448 PMCid:2150716
43. M. Yebra, A. M. Montgomery, G. R. Diaferia, T. Kaido, S. Silleti, B. Perez, M. L. Just, S. Hildbrand, R. Hurford, E. Florkiewicz, M. Tessier-Lavigne & V. Cirulli: Recognition of the Neural Chemoattractant Netrin-1 by Integrins α6β4 and α3β1 Regulates Epithelial Cell Adhesion and Migration. Dev Cell 5, 695-707 (2003)
doi:10.1016/S1534-5807(03)00330-7
PMid:14602071
44. S. Saleem, J. Li, F. Fellows, C. G. Goodyer & R. Wang: β1 integrin associates with FAK to propagate a MAPK/ERK signal for human fetal islet cell growth and survival. Diabetes, Suppl(1) 55, A78 (2006)
45. T. Kaido, B. Perez, M. Yebra, J. Hill, V. Cirulli, A. Hayek, & A. M. Montgomery: αv-Integrin Utilization in Human β-Cell Adhesion, Spreading, and Motility. J Biol Chem 279(17), 17731-17737 (2004)
doi:10.1074/jbc.M308425200
PMid:14766759
46. U. Dahl, A. Sjodin & H. Semb: Cadherins Regulate Aggregation of Pancreatic Beta-Cells in Vivo. Development 122, 2895-2902 (1996)
47. F. Esni, I. B. Taljedi, A. K. Perl, H. Cremer, G. Christofori & H. Semb: Neural Cell Adhesion Molecule (N-CAM) is Required for Cell Type Segregation and Normal Ultrastructure in Pancreatic Islets. J Cell Biol 144, 325-337 (1994)
doi:10.1083/jcb.144.2.325
PMid:9922458 PMCid:2132899
48. V. Cirulli, D. Baetens, U. Rutishauser, P. A. Halban, L. Orci & D. A. Rouiller: Expression of Neural Cell Adhesion Molecules (N-CAM) in Rat Islets and its Role in Islet Cell Type Segregation. J Cell Sci 107, 1429-1436 (1994)
49. R. Wang & L. Rosenberg: Maintenance of β-cell function and survival following islet isolation requires re-establishment of the islet-matrix relationship. J Endocrinol 163,181-190 (1999)
doi:10.1677/joe.0.1630181
PMid:10556766
50. R. Wang, J. Li & L. Rosenberg: Factors mediating the transdifferentiation of islets of Langerhans to duct epithelial-like structures. J Endocrinol 171, 309-318 (2001)
doi:10.1677/joe.0.1710309
PMid:11691651
51. F. Ris, E. Hammar, D. Bosco, C. Pilloud, K. Maedler, M. Y. Donath, J. Oberholzer, E. Zeender, P. Morel, D. Rouiller & P. Halban: Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells in vitro. Diabetologia 45, 841-850 (2002)
doi:10.1007/s00125-002-0840-7
PMid:12107728
52. R. Montessano, P. Mouron, M. Amherdt, & L. Orci: Collagen Matrix Promotes Pancreatic Endocrine Cell Reorganization of Monolayers into Islet-like Organoids. J Cell Biol 97, 935-939 (1983)
doi:10.1083/jcb.97.3.935
PMid:6350323 PMCid:2112577
53. S. Kantengwa, D. Beatens, K. Sadoul, C. A. Buck, P. A. Halban & D. G. Rouiller: Identification and characterization of α3β1 on primary and transformed rat islet cells. Exp Cell Res 237, 394-402 (1997)
doi:10.1006/excr.1997.3803
PMid:9434635
54. D. Bosco, P. Meda, P. A. Halban & D. G. Rouiller: Importance of cell-matrix interactions in rat islet β cell secretion in vitro: role of α6β1 integrin. Diabetes 49, 233-243 (2000)
doi:10.2337/diabetes.49.2.233
PMid:10868940
55. G. Pernaud, E. Hammar, D. G. Rouiller, M. Armanet, P. A. Halban & D. Bosco: Blockade of β1 Integrin-Laminin-5 Interactions affects spreading and insulin secretion of rat β-cells attached on extracellular matrix. Diabetes 55, 1413-1420 (2006)
doi:10.2337/db05-1388
PMid:16644699
56. M. Krishnamurthy, J. Li, M. Al-Masri & R. Wang: Expression and function of αβ1 integrins in pancreatic beta (INS-1) cells. J Cell Commun Signal, DOI: 10.1007/s12079-008-0030-6 (2008)
57. T. Kaido, M. Yebra, V. Cirulli, C. Rhodes, G. Diaferia & A. M. Montgomery: Impact of defined matrix interations on insulin production by cultured human β-cells. Diabetes 55, 2723-2729 (2006)
doi:10.2337/db06-0120
PMid:17003336
58. G. G. M. Pinske, W. P. Bouwman, R. Jiwan-lalai, O. T. Terpstra, J. A. Bruijn & E. deHeer: Integrin signaling via RGD peptides and anti-β1 antibodies confers resistance to apoptosis in islets of langerhans. Diabetes 55, 312-317 (2006)
doi:10.2337/diabetes.55.02.06.db04-0195
PMid:16443762
59. S. Merani & A. M. J. Shapiro: Review: Current Status of Pancreatic Islet Transplantation. Clin Sci. 110, 611-625 (2006)
doi:10.1042/CS20050342
PMid:16689680
60. A. N. Balamurugan, R. Bottino, N. Giannoukakis & C. Smetanka: Prospectives and Challenges of Islet Transplantation for the Therapy of Autoimmune Diabetes. Pancreas. 32(3), 231-243 (2006)
doi:10.1097/01.mpa.0000203961.16630.2f
PMid:16628077
61. E. A. Ryan, D. Bigam & A. M. J. Shapiro: Current indices for pancreas or islet transplantation. Diabetes, Obes Metab 8(1), 1-7 (2006).
doi:10.1111/j.1463-1326.2004.00460.x
62. A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman & R. V. Rajotte: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 27, 230-238 (2000)
doi:10.1056/NEJM200007273430401
PMid:10911004
63. R. Gao, J. Ustinov, O. Korsgren & T Otonkoski: Effects of immunosuppressive drugs on in vitro neogenesis of human islets: Mycophenolate Mofetil inhibits the proliferation of ductal cells. Am J Transplant 7(4), 1021-1026 (2007)
doi:10.1111/j.1600-6143.2006.01728.x
PMid:17391142
64. S. Bonner-Weir & A. Sharma: Pancreatic stem cells. J Pathol 197, 519-526 (2002)
doi:10.1002/path.1158
PMid:12115867
65. J. J. Heit & S. K. Kim: Embryonic stem cells and islet replacement in diabetes mellitus. Pediatr Diabetes 5, 5-15 (2004)
doi:10.1111/j.1399-543X.2004.00074.x
PMid:15601369
66. S. Bonner-Weir: Perspective: postnatal pancreatic b cell growth. Endocrinology 141, 1926-9 (2000)
doi:10.1210/en.141.6.1926
PMid:10830272
67. L. Rosenberg: Induction of islet cell neogenesis in the adult pancreas: the partial duct obstruction model. Microsc Res Tech 43, 337-46 (1998)
doi:10.1002/(SICI)1097-0029(19981115)43:4<337::AID-JEMT8>3.0.CO;2-U
PMid:9849975
68. V. K. Ramiya, M. Maraist, K. E. Arfors, D. A. Schatz, A. B. Peck & J. G. Cornelius: Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nature Med 6, 278-82 (2000)
doi:10.1038/73128
PMid:10700229
69. S. Bonner-Weir, M. Taneja, G. C. Weir, K. Tatarkiewicz, K. H. Song & A. Sharma A: In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97, 7999-8004 (2000)
doi:10.1073/pnas.97.14.7999
70. M. R. Katdare, R. R. Bhonde & P. B. Parab: Analysis of morphological and functional maturation of neoislets generated in vitro from pancreatic ductal cells and their suitability for islet banking and transplantation. J Endocrinol 182, 105-12 (2004)
doi:10.1677/joe.0.1820105
PMid:15225135
71. M. Banerjee & R. Bhonde: Islet generation from intra islet precursor cells of diabetic pancreas: in vitro studies depicting in vivo differentiation. JOP 4, 137-45 (2003)
72. M. Kanitkar & R. Bhonde: Existence of islet regenerating factors within the pancreas. Rev Diab Stud 1, 185-92 (2004)
doi:10.1900/RDS.2004.1.185
PMid:17491703 PMCid:1783689
73. Y. Dor, J. Brown, O. I. Martinez & D. A. Melton: Adult pancreatic beta-cells are formed by self-duplication rather than stemcell differentiation. Nature 429, 41-6 (2004)
doi:10.1038/nature02520
PMid:15129273
74. S. Bonner-Weir: Two pathways of beta-cell growth in the regenerating rat pancreas: Implications for islet transplantation. Diabetes Nutr Metab 5, 1-3 (1992)
75. I. Swenne: Pancreatic beta-cell growth and diabetes mellitus. Diabetologia 35, 193-201 (1992)
doi:10.1007/BF00400917
PMid:1563578
76. F. S. Smith, K. M. Rosen, L. Villa-Komaro, G. C. Weir & S. Bonner-Weir: Enhanced insulin-like growth factor I gene expression in the regenerating rat pancreas. Proc Natl Acad Sci USA 88, 6152-6 (1991)
doi:10.1073/pnas.88.14.6152
77. C. Lucas-Clerc, C. Massart, J. P. Campion, B. Launois & M. Nicol: Long-term culture of human pancreatic islets in an extracellular matrix: morphological and metabolic effects. Mol Cell Endocrinol 94, 9-20 (1993)
doi:10.1016/0303-7207(93)90046-M
PMid:8375579
78. N Nagata, A Iwanaga, K Inoue and Y Tabata: Co-culture of extracellular matrix suppresses the cell death of rat pancreatic islets. Journal of Biomaterials Sciences 13(5): 579-590 (2004)
doi:10.1163/15685620260178418
PMid:12182560
79. T. Xiaohui, X. Wunjun, P. Xinlun, T. Yan, T. Puxun & F. Xinshun: Effect of small intestinal submucosa on islet recovery and function in vitro culture. Hep Panc Disease Int 4(4), 524-529 (2005)
80. T. Xiaohui, X. Wunjun, D. Xiaoming, P. Xinlu, T. Yan, T. Puxun & F. Xinshun: Small Intestinal Submucosa Improves Islet Survival and Function in vitro culture. Transplant Proc 38, 1552-1558 (2006)
doi:10.1016/j.transproceed.2006.02.134
PMid:16797356
81. J. R.T. Lakey, E. J. Woods, M. A. J. Zieger, J. G. Avila, W. A. Geary, S. L. Voytik-Harbin & J. K. Critser: Improved islet survival and in vitro function using solubilized small intestinal submucosa. Cell Tissue Bank 2, 217-224 (2001)
doi:10.1023/A:1021171200127
PMid:15256904
82. S. Merani & A. M. J. Shapiro: Current status of pancreatic islet transplantation. Clin Sci 110, 611-625 (2006)
doi:10.1042/CS20050342
PMid:16689680
83. P. McShane, W. J. Teague & H. Contractor: Acta Diabetol 40:208, 2003
84. S.J. Hughes, P. McShane, H. H. Contractor, D. W. R. Gray, A. Clark, & P.R.V. Johnson: Comparison of the Collagen VI Content Within the Islet-Exocrine Interface of the Head, Body, and Tail Regions of the Human Pancreas. Transplant Proc 37, 3444-3445 (2005)
doi:10.1016/j.transproceed.2005.09.027
PMid:16298623
85. F. Jiang, G. Naselli & L. C. Harrison: Distinct Distribution of Laminin and Its Integrin Receptors in the Pancreas. J Histochem Cytochem 50, 1625-1632 (2002)
86. S. Geutskens, F. Homo-Delarche, J. Pleau, S. Durant, H. A. Drexhage & W. Savino: Extracellular matrix distribution and islet morphology in the early postnatal pancreas: anomalies in the non-obese diabetic mouse. Cell Tissue Res 318, 579-589 (2004)
doi:10.1007/s00441-004-0989-0
PMid:15480796
87. Y. P. Lu, T. Ishiwata & G. Asano: Lumican expression in alpha cells of islets in pancreas and pancreatic cancer cells. J Pathology 196, 324-330 (2002)
doi:10.1002/path.1037
PMid:11857496
88. R. N. Wang, S. Paraskevas, & L. Rosenberg: Characterization of Integrin Expression in Islets Isolated from Hamster, Canine, Porcine, and Human Pancreas. J Histochem Cytochem 47(4), 499-506 (1999)
89. G. Nikolova, N. Jabs, I. Konstantinova, A. Domogatskaya, K. Tryggvason, L. Sorokin, R. Fässler, G. Gu, H. P. Gerber, N. Ferrara, D. A. Melton & E. Lammert: The vascular basement membrane: a niche for insulin gene expression and beta cell proliferation. Dev Cell 10, 397-405 (2006)
doi:10.1016/j.devcel.2006.01.015
PMid:16516842
90. E. Lammert, O. Cleaver & D. A. Melton: Induction of pancreatic differentiation by signals from blood vessels. Science 294, 564-567 (2001)
doi:10.1126/science.1064344
PMid:11577200
91. H. Yoshitomi & K. S. Zaret: Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131(4), 807-817 (2004)
doi:10.1242/dev.00960
PMid:14736742
92. A. I. Silva, A. N. de Matos, I. G. Brons & M. Mateus: An Overview on the Development of a Bio-Artificial Pancreas as a Treatment of Insulin Dependent Diabetes Mellitus. Med Res Reviews 26(2), 181-222 (2006)
doi:10.1002/med.20047
PMid:16342061
93. A. S. Narang & R. I. Mahato: Biological and Biomaterial Approaches for Improved Islet Transplantation. Pharmacol Reviews 58(2), 194-243 (2006)
doi:10.1124/pr.58.2.6
PMid:16714486
94. S. Kizilel, M. Garfinkel & E. Opara: The Bioartificial Pancreas: Progress and Challenges. Diabetes Technol Ther 7, 968-985 (2005)
doi:10.1089/dia.2005.7.968
95. M. De Groot, T. A. Schuurs & R. van Schilfgaarde: Causes of limited survival of microencapsulated pancreatic islet grafts. J Surg Res 121, 141-150 (2004)
doi:10.1016/j.jss.2004.02.018
PMid:15313388
96. K. Edamura, H. Ohgawara, K. Nasu, Y. Iwami, A. Sato, S. Ishikawa, N. Matsuki, K. Ono, H. Ogawa & N. Sasaki: Effect of the extracellular matrix on pancreatic endocrine cell function and its biocompatibility in dogs. Cell Transplant 10(4-5), 493-8 (2001)
97. D. M. Salvay, C. B. Rives, X. Zhang, F. Chen, D. B. Kaufman,W. L. Lowe Jr., & L. D. Shea: Extracellular Matrix Protein-Coated Scaffolds Promote the Reversal of Diabetes After Extrahepatic Islet Transplantation. Transplantation 85, 1456-1464 (2008)
doi:10.1097/TP.0b013e31816fc0ea
PMid:18497687
98. H. Blomeier, X. Zhang, C. Rives, M. Brissova, E. Hughes,M. Baker, A. C. Powers, D. B. Kaufman, L. D. Shea & W. L. Lowe, Jr.: Polymer Scaffolds as Synthetic Microenvironments for Extrahepatic Islet Transplantation. Transplantation 82, 452-459 (2006)
doi:10.1097/01.tp.0000231708.19937.21
PMid:16926587
99. L. M. Weber, K. N. Hayda, K. Haskins & K. S. Anseth: The effects of cell-matrix interactions on encapsulated β-cell function within hydrogels functionalized with matrix-derived adhesive peptides. Biomaterials 28, 3004-3011 (2007)
doi:10.1016/j.biomaterials.2007.03.005
PMid:17391752
100. S. A. Safley, L. M. Kapp, C. Tucker-Burden, B. Hering, J. A. Kapp & C. J. Weber: Inhibition of cellular immune responses to encapsulated porcine islet xenografts by simultaneous blockade of two different costimulatory pathways. Transplantation 79, 409-418 (2005)
doi:10.1097/01.TP.0000150021.06027.DC
PMid:15729166
101. U. Siebers, T. Zekorn, R. G. Bretzel, M. Renardy, P. Zschocke, H. Planck & K. Federlin: Bioartificial pancreas: Islet survival and interleukin-1 action. Transplant Proc 22, 2035-2036 (1990)
102. S. S. Maria-Engler, M. Mares-Guia, M. L. C. Correa, E. M. C. Oliveira, C. A. M. Aita, K. Krogh, T. Genzini, M. P. Miranda, M. Ribeiro, L. Vilela, I. L. Noronha, F. G. Eliaschewitz & M.C. Sogayar: Microencapsulation and tissue engineering as an alternative treatment of diabetes. Brazilian J Med Biol Res. 34, 691-697 (2001)
doi:10.1590/S0100-879X2001000600001
PMid:11378656
103. P. De Vos, B. De Haan & R. Van Schilfgaard: Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules. Biomaterials 18, 273-278 (1997)
doi:10.1016/S0142-9612(96)00135-4
PMid:9031730
104. R. van Schilfgaarde & P. De Vos: Factors influencing the properties and performance of microcapsules for immunoprotection of pancreatic islets. J Mol Med 77, 199-205 (1999)
doi:10.1007/s001090050336
PMid:9930963
105. K. R. Knight, Y. Uda, M. W. Findlay, D. L. Brown, K. J. Cronin, E. Jamieson, T. Tai, E. Keramidaris, A. J. Penington, J. Rophael, L. C. Harrison & W. A. Morrison: Vascularized tissue-engineered chambers promote survival and function of transplanted islets and improve glycemic control. FASEB J, 565-567 (2006)
106. S. Y. Chae, S. W. Kim & Y. H. Bae: Effect of cross-linked hemoglobin on functionality and viability of microencapsulated pancreatic islets. Tissue Eng 8, 379-94 (2002)
doi:10.1089/107632702760184655
PMid:12167225
107. K. Bloch, E. Papismedov, K. Yavriyants, M. Vorobeychik, S. Beer & P. Vardi: Immobilized microalgal cells as an oxygen supply system for encapsulated pancreatic islets: a feasibility study. Artif Organs 30(9), 715-718 (2006)
doi:10.1111/j.1525-1594.2006.00289.x
PMid:16934101
108. H. Wu, E. S. Avgoustiniatos, L. Swette, S. Bonner-Weir, G. C. Weir & C. K. Colton: In situ electrochemical oxygen generation with an immunoisolation device. Ann N Y Acad Sci 875, 15-25 (1999)
doi:10.1111/j.1749-6632.1999.tb08497.x
PMid:10415561
109. J. G. Lees, S. A. Lim, T. Croll, G. Williams, S. Lui, J. Cooper-White, L. R. McQuade, B. Mathiyalagan & B. E. Tuch: Transplantation of 3D scaffolds seeded with human embryonic stem cells: biological features of surrogate tissue and teratoma-forming potential. Regen Med 2(3), 289-300 (2007)
doi:10.2217/17460751.2.3.289
PMid:17511565
110. J. L. Foster, G. Williams, L. J. Williams & B. E. Tuch: Differentiation of transplanted microencapsulated fetal pancreatic cells. Transplantation 83(11),1440-8 (2007)
doi:10.1097/01.tp.0000264555.46417.7d
PMid:17565317
111. A. E. Berman, N. I. Kozlova & G. E. Morozevich: Integrins: Structure and Signaling. Biochemistry 68, 1284-1299 (2003)
112. J. A. Eble: Molecular Biology Intelligence Uni. Integrin-ligand interactions (Eble JA, and Kunn K eds.) Chapman and Hall, New York, pp. 1-40 (1997)
113. L. J. Green, A. P. Mould & M. J. Humphries: The Integrin Beta Subunit. Int J Biochem Cell Biol 30, 179-184 (1998)
doi:10.1016/S1357-2725(97)00107-6
114. M. J. Humphries: Integrin Structure. Biochem Soc Trans 28, 311-339 (2000)
doi:10.1042/0300-5127:0280311
PMid:10961914
115. M. Krishnamurthy, J. Li, M. Al-Masri & R. Wang: Dynamic Interactions between α3β1 and Collagen I and IV Matrices: Modulation of Beta Cell Adhesion, Survival and Function. Diabetes, Suppl(1) 57, A445 (2008)
Abbreviations: BAP: bioartifical endocrine pancreas; BM: basement membrane; e18: embryonic day 18; ECM: extracellular matrix; EGF: epidermal growth factor; LPA: lysophosphatidic acid; MIN6 cells: mouse insulinoma 6 cell line; PDGF: platelet derived growth; factor; SIS: small intestinal submucosa
Key Words: Extracellular matrix, Integrins, Development, Function, Bioartificial Pancreas, Review
Send correspondence to: Rennian Wang, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, Ontario, N6C 2V5, Canada, Tel: 519-685-8500 ext. 55098, Fax: 519-685-8186, E-mail:rwang@uwo.ca