Objective: We sought to assess the cardiac protective effects after MI of (1) PC differentiated directly into cardiomyocytes (CM) and endothelial cells (EC) to the site of injury, or (2) paracrine factors released from PC.
Methods: These concepts were evaluated by using iPSC-derived PC genetically modified to express the herpes simplex virus thymidine kinase (TK) under the control of cardiomyocyte (NCX1) or endothelial cell (VE-cadherin) specific promoters. PC expressing the TK permitted ablation at the first week or the third week by iv ganciclovir (GCV). If GCV applied at the first week, but not at the third week, altered cardiac function, we would conclude that myocardial contractile recovery depends on CM and EC-derived from iPSC. If the beneficial effects on cardiac function persisted after GCV was given at the third week, we would surmise that the PC effect was via by a paracrine action. MI created by ligation of LAD, the cell patch with PC was applied to the scarred myocardium. Rats were treated with GCV at 1 or 3 weeks to ablate implanted PC. Echocardiography, vessel density, and histological analysis were used to obtain endpoints for this study.
Result:In vivo: The levels of IGF-1α and VEGF released from ischemic tissues were significant higher in the cell patch group. Heart function, infarction size, and vessel density were significantly improved after cell patch treatment. However, this beneficial effect on cardiac function was completely abolished in the group given GCV at week 1, but only partially abolished in the group given GCV at week 3 compared to the untreated cell patch group.
Conclusions: Taken together, these data support our conclusion that iPSC-derived cardiovascular lineages (CM and EC) contribute directly to an improved cardiac performance and attenuated remodeling, and that paracrine factors also play a supporting role in the restoration of heart function after MI.