Abstract 1117: Genetic Modification with Sonic Hedgehog Mitigates Aging-induced EPC Dysfunction and Augments Therapeutic Angiogenesis of Endogenous EPCs following Acute Myocardial Infarction

Background: Clinical trials of autologous stem/progenitor cell transplantation in ischemic heart diseases are now on-going. Simultaneously, mounting evidence suggests that age related decreases in EPC number or function may limit this therapeutic approach. We tested the hypothesis that gene modification of aged EPCs, using the embryonic signaling molecule, sonic hedgehog (Shh), may ameliorate aging induced dysfunction of EPCs and thereby enhance the reparative effect of autologous EPCs. Methods and Results: EPCs from aged mice (24 m.o.), previously shown to exhibit impaired potency, were used and compared to EPCs from young (3 m.o.) mice. Shh gene transfer significantly improved proliferation and anti-apoptosis activities vs. empty vector transfected (EV) aged EPCs, up to a similar level of EV young EPCs. Next, we evaluated the therapeutic effect of Shh-gene-modified aged EPCs (Shh-EPC) vs. EV aged EPCs (EV-EPC) vs. PBS (Ctrl) injection in a mouse AMI model. Shh-EPCs or EV-EPCs (1000 cells) or PBS was injected into the ischemic myocardium immediately following MI. Scar length in the infarcted LV 14 days after surgery was significantly reduced in the Shh-EPC group compared to the EV-EPC group and the PBS group associated with increased capillary density in the peri-infarct area. In addition, Ki67 positive cardiomyocytes were observed with increased frequency in the Shh-EPC group. In Tie2-LacZ BMT mice, beta-gal positive-endogenous BM-derived EPC recruitment was significantly greater in ischemic myocardium in the Shh-EPC group than that in the EV-EPC group. Differentiation of recruited EPCs into endothelial cells or cardiomyocytes was also observed more frequently in the Shh-EPC group compared to the EV-EPC group. These data suggest that cardiac repair was induced by a small number of transplanted Shh gene modified aged EPCs with the increased paracrine effects following MI. Conclusion: Shh gene transfer to aged EPCs ameliorates aging-induced EPC dysfunction. Intramyocardial transplantation of Shh-gene-modified aged EPCs augments therapeutic efficacy for myocardial repair following MI by promoting endogenous EPC recruitment. Shh gene modified EPCs may represent a second-generation EPC-based therapeutic strategy in ischemic heart disease.