Regenerative potential of mouse embryonic stem cell-derived PDGFRα+ cardiac lineage committed cells in infarcted myocardium.

ABSTRACT

BACKGROUND: Pluripotent stem cell-derived cardiomyocytes (CMs) have become one of the most attractive cellular resources for cell-based therapy to rescue damaged cardiac tissue. AIM: We investigated the regenerative potential of mouse embryonic stem cell (ESC)-derived platelet-derived growth factor receptor-α (DGFRα)+ cardiac lineage-committed cells (CLCs), which have a proliferative capacity but are in a morphologically and functionally immature state compared with differentiated CMs. METHODS: We induced mouse ESCs into PDGFRα+ CLCs and αMHC+ CMs using a combination of the small molecule cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. We implanted PDGFRα+ CLCs and differentiated αMHC+ CMs into a myocardial infarction (MI) murine model and performed functional analysis using transthoracic echocardiography (TTE) and histologic analysis. RESULTS: Compared with the untreated MI hearts, the anterior and septal regional wall motion and systolic functional parameters were notably and similarly improved in the MI hearts implanted with PDGFRα+ CLCs and αMHC+ CMs based on TTE. In histologic analysis, the untreated MI hearts contained a thinner ventricular wall than did the controls, while the ventricular walls of MI hearts implanted with PDGFRα+ CLCs and αMHC+ CMs were similarly thicker compared with that of the untreated MI hearts. Furthermore, implanted PDGFRα+ CLCs aligned and integrated with host CMs and were mostly differentiated into α-actinin+ CMs, and they did not convert into CD31+ endothelial cells or αSMA+ mural cells. CONCLUSION: PDGFRα+ CLCs from mouse ESCs exhibiting proliferative capacity showed a regenerative effect in infarcted myocardium. Therefore, mouse ESC-derived PDGFRα+ CLCs may represent a potential cellular resource for cardiac regeneration.