[Frontiers in Bioscience 15, 854-871, June 1, 2010]

Genetic modification of ex-vivo expanded stem cells for clinical application

Reeva Aggarwal, Vincent J Pompili, Hiranmoy Das

Cardiovascular Stem Cell Research Laboratory, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. HSC regulation and microenvironment
3.1. Niche cells
3.2. Niche signaling
3.3. Niche adhesion molecules
3.4. Chemical regulation of niche 4. Hematopoietic stem cell Expansion
4.1. Factors regulating ex-vivo expansion
4.1.1. Interleukin-3
4.1.2. Interleukin-6
4.1.3. Thrombopoietin
4.1.4. Fetal liver tyrosine kinase-3 ligand
4.1.5. Stem cell Factor
4.1.6. Signaling molecules
5. Genetic modification of Stem Cells
5.1. Viral methods
5.1.1. Retroviruses
5.1.2. Lentiviruses
5.1.3. Adeno-associated viruses
5.2. Non-viral methods
5.2.1. Calcium phosphate
5.2.2. Lipofection
5.2.3. Electroporation
5.2.4. Nucleofection
6. Stem cell therapy for ischemic diseases
6.1. Role of pro-angiogenic factors
6.1.1. Vascular endothelial growth factor
6.1.2. Platelet derived growth factor
6.1.3. Fibroblast growth factor-2
6.1.4. Placental growth factor
6.1.5. Hepatocyte growth factor
7. Conclusions and future directions
8. Acknowledgements
9. References

1. ABSTRACT

Stem cell therapy is currently considered as an important regime for repairing, replacing or enhancing the biological functions of the damaged tissues. Among adult stem cells, hematopoietic stem cells (HSCs) are commonly used for cure of hematological disorders. However, the number of HSCs obtained from sources like bone marrow, peripheral or umbilical cord blood is not sufficient for routine clinical application. Thus, ex-vivo expansion of HSCs becomes critically important. Ex-vivo culture and expansion of stem cells are challenging, as stem cells differentiate in culture rather than self-renew. Lack of clarity about the factors responsible for quiescence and differentiation of HSCs, investigators struggled to optimize conditions for ex vivo expansion. As we understand better, various strategies can be incorporated to mimic in vivo conditions for successful expansion of stem cells. However, characterization and biological functionality should also be tested for expanded stem cells prior to clinical application. To treat ischemia by enhancing therapeutic angiogenesis and neo-vascularization, the role of genetic modification of HSCs with pro-angiogenic factors is the focus of this review.