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Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Cell Anatomy | Integrative Biology
Peripheral artery disease is an atherosclerotic disease that causes limb ischemia and has few effective treatments. Stem cell therapy is a promising treatment option, but concomitant diabetes may limit its effectiveness. The purpose of this study was to evaluate the therapeutic potential of skeletal muscle pericytes to augment postischemic neovascularization following the induction of limb ischemia in wild type and type 2 diabetic (T2DM) mice. The hypothesis was that diabetes impairs the ability of skeletal muscle pericytes to augment postischemic neovascularization and differentiate in vivo. Pericytes were isolated via fluorescence activated cell sorting for CD45-CD34-CD146+ cells, and pericyte phenotype was confirmed via surface marker expression, gene expression, and in vitro differentiation potential. Wild type C57BL/6 (n=12) and leptin receptor deficient db/db T2DM (n=10) mice underwent unilateral femoral artery ligation to induce limb ischemia. Twenty-four hours post-ligation, pericytes or vehicle control were transplanted into the muscles of the ischemic hindlimbs. Postischemic neovascularization was assessed via foot blood flow at pre-surgery, post-surgery, and postoperative days 3, 7, 14, 21, and 28 using laser Doppler perfusion imaging. Differences in gene expression were determined using t-tests; differences in blood flow were determined using linear mixed models. CD45-CD34-CD146+ pericytes were positive for mesenchymal stem cell markers CD90 (74%) and CD105 (65%) and weakly positive for the pericyte marker PDGFRβ (42%) and the endothelial cell marker CD144 (36%). Pericytes transdifferentiated into skeletal myocytes, adipocytes, osteocytes, and endothelial cells in vitro. Pericytes had significantly (pSca1 (4.0-fold) gene expression, downregulated CD31 (0.2-fold) gene expression, and no difference in MyoD (1.0-fold), Pax3 (1.3-fold), or Pax7 (1.0-fold) expression. Blood flow recovery in wild type mice was significantly higher after pericyte transplantation than after vehicle control (p=0.04; 79.3±5% vs. 61.9±5% at postoperative day 28). Blood flow recovery in T2DM mice after pericyte transplantation was not different than after vehicle control (p=0.51; 48.6% vs. 46.3±5% at postoperative day 28). There was no effect of pericyte transplant on angiogenesis in wild type or T2DM mice. Pericyte transplantation enhanced collateral artery enlargement compared to control transplantation in wild type (26.7±2 μm vs. 22.3±1 μm, p=0.03), but not T2DM mice (20.4±1.4 μm vs. 18.5±1.2 μm, p=0.14). In vivo, there was greater pericyte incorporation into collateral arteries in wild type than in T2DM mice; and transplanted pericytes differentiated into Schwann cells in both wild type and T2DM mice. In conclusion, T2DM impairs the ability of pericytes to augment neovascularization via decreased collateral artery enlargement and impaired engraftment into collateral vessels. Further study is required to determine the mechanism by which T2DM impairs pericyte cell therapy.
Hayes, Katherine E., "THE EFFECT OF PERICYTE CELL THERAPY ON POSTISCHEMIC NEOVASCULARIZATION IN WILD TYPE AND TYPE 2 DIABETIC MICE" (2017). Doctoral Dissertations. 1013.