Xenogeneic Stem Cell–Induced Cardiac Progenitor Cells Regenerated Infarcted Myocardium in Rat Model

Purpose: We aim to investigate the role of stem cell–based regenerative medicine to repair or regrow the infarcted myocardium and restore normal cardiac homeostasis. Methods: WIKI4-treated cells were tested for in vitro differentiation into myocytes by gene and protein expression. A myocardial infarction (MI) model was established, cells were transplanted, and cardiac function was assessed by echocardiography. Histological evaluation of the harvested heart was performed to evaluate the cardiac regeneration. Results: These pre-differentiated cardiomyocytes were assessed for the presence of cardiac markers using immunocytochemical staining for Gata-4, Alpha actinin, and Myosin heavy chain, and gene expression analysis also showed that these cells are expressing cardiomyogenic markers. Hearts transplanted with WIKI4-treated mesenchymal stem cells (MSCs) significantly (***P<0.001) improved the cardiac systolic and diastolic dimension, end-systolic, diastolic, and stroke volume, ejection fraction, and fraction shortening as compared to the MI group after two and four weeks. Fibrotic area and left ventricular wall thickness significantly (***P<0.001) improved in WIKI4-treated group as compared to the control group. Patches of normal myocytes were observed in the infarct zone showing that induced cardiac progenitor cells regenerated cardiomyocytes replacing the infarcted scar, as evident from the co-localization of fluorescently labeled cells and cardiac proteins in immunohistochemical staining. Conclusion: This study put forth a valuable approach by small molecules to induce differentiation of MSCs into cardiomyocytes, which upon in vivo transplantation regenerated the infarcted heart. These findings will lead to the development of a novel approach for modified cellular therapy and may increase the probability of better myocardial regeneration. Lay Summary: Cardiovascular diseases (CVD) are the leading causes of morbidity and mortality. The indigenous capability of the myocardium to meet the degeneration is limited. Currently, available therapeutic options for the treatment of CVD are limited and provide solutions to reduce the symptoms. To investigate the role of stem cell–based repairing or regrowing the myocardium and restoring normal cardiac homeostasis, WIKI4-treated cells were tested for in vitro differentiation into myocytes by gene and protein expression. Treatment of human bone marrow–derived mesenchymal stem cells with WIKI4 induced differentiation of MSCs into the cardiomyogenic lineage. Xenogeneic MSCs and their derivatives in form of induced cardiac progenitors when implanted into the infarcted rat’s heart showed survival, distribution, integration, and differentiation into myogenic lineage, maintained the thickness of the left ventricular wall, infarct area was reduced, and hearts performed better function.