Ischemic disease remains a major cause of morbidity and mortality in the USA and worldwide, and is particularly problematic in diabetics. Cell therapies have been demonstrated to enhance local vascularization and perfusion in a variety of models, but patient improvement in the clinical trials to date has been modest. This likely relates to the small percentage of transplanted cells that engraft successfully and participate in rebuilding the vasculature, and the current limited knowledge of the mechanism(s) by which the cells exert their effects. The specific hypothesis to be addressed in this project is that the ability of transplanted endothelial progenitor cells to build a vascular network and relieve tissue ischemia can be dramatically enhanced by providing a sustained release of appropriately primed cells into the hypoxic tissue from a biomaterial vehicle. This hypothesis will be evaluated with the following set of aims: (1) Determine if appropriate design of a vehicle microenvironment can regulate endothelial progenitor cell gene expression, migration through the material and dispersion into the surrounding tissue, (2) Quantify the ability of a sustained delivery and tissue repopulation by endothelial progenitor cells to relieve acute and chronic peripheral ischemia in SCID mice, and determine the mechanism(s) of this effect, and (3) Examine the ability of material-mediated endothelial progenitor cell delivery to enhance recovery from peripheral ischemia in the context of diabetes, using a STZ induced mouse and an alloxan-induced rabbit model of diabetes. The data and systems arising from these studies may impact several areas of biology and engineering research, and lead to clinical strategies to revascularize ischemic tissue. Perhaps most importantly, a new approach will be developed in this project that aims to effectively repopulate ischemic tissues with cells competent to orchestrate neovascularization. This approach will be investigated in the context of the peripheral ischemia, but this approach would also find utility in the treatment of coronary artery disease and other situations involving tissue ischemia. We anticipate that autologous cells would initially be used in these applications, and the clinical experience developed to date in endothelial progenitor isolation and expansion will directly apply to the cell source aspects of this approach. These studies will also improve the current understanding of the role of the two cell populations - EPCs and OECs in vascularization, and this may lead to completely new strategies of neovascularization in the future.

Public Health Relevance

Critical limb ischemia affects large number of Americans each year, and is a leading cause of limb amputation. The goal of these studies is to create a new approach to transplant cells that can potentially reverse the loss of blood flow to afflicted limbs. The materials developed in this project may provide a more practical and effective means of using stem cell populations to cure these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Lundberg, Martha
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Harvard University
Biomedical Engineering
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United States
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Anderson, Erin M; Silva, Eduardo A; Hao, Yibai et al. (2017) VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits. J Vasc Res 54:288-298
Kwee, Brian J; Mooney, David J (2015) Manipulating the intersection of angiogenesis and inflammation. Ann Biomed Eng 43:628-40
Anderson, Erin M; Kwee, Brian J; Lewin, Sarah A et al. (2015) Local delivery of VEGF and SDF enhances endothelial progenitor cell recruitment and resultant recovery from ischemia. Tissue Eng Part A 21:1217-27
Schmidt-Bleek, Katharina; Kwee, Brian J; Mooney, David J et al. (2015) Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis. Tissue Eng Part B Rev 21:354-64
Anderson, Erin M; Mooney, David J (2015) The Combination of Vascular Endothelial Growth Factor and Stromal Cell-Derived Factor Induces Superior Angiogenic Sprouting by Outgrowth Endothelial Cells. J Vasc Res 52:62-9
Roche, Ellen T; Hastings, Conn L; Lewin, Sarah A et al. (2014) Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart. Biomaterials 35:6850-6858
Silva, Eduardo A; Eseonu, Chikezie; Mooney, David J (2014) Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia. Angiogenesis 17:617-30
Kaigler, Darnell; Silva, Eduardo A; Mooney, David J (2013) Guided bone regeneration using injectable vascular endothelial growth factor delivery gel. J Periodontol 84:230-8
Brudno, Yevgeny; Ennett-Shepard, Alessandra B; Chen, Ruth R et al. (2013) Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors. Biomaterials 34:9201-9
Shamis, Yulia; Silva, Eduardo A; Hewitt, Kyle J et al. (2013) Fibroblasts derived from human pluripotent stem cells activate angiogenic responses in vitro and in vivo. PLoS One 8:e83755

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