Transplanted Induced Pluripotent Stem Cells Mitigate Oxidative Stress and Improve Cardiac Function through the Akt Cell Survival Pathway in Diabetic Cardiomyopathy

Abstract

Recent evidence suggests transplanted stem cells improve left ventricular function in diabetic induced cardiomyopathy (DICM). However, little is known about the mechanisms by which induced pluripotent stem (iPS) cells or factors released from these cells inhibit adverse cardiac remodeling in DICM. The present study was designed to determine molecular mediators and pathways regulated by transplanted iPS cells and their conditioned media (CM) in DICM. Animals were divided into four experimental groups such as control, streptozotocin (STZ), STZ+iPS-CM, and STZ+iPS cells. Experimental diabetes was induced in C57BL/6 mice by intraperitoneal STZ injections (100 mg/kg body weight for 2 consecutive days). Following STZ injections, iPS cells or CM was given intravenously for 3 consecutive days. Animals were humanely killed, and hearts were harvested at D14. Animals transplanted with iPS cells or CM demonstrated a significant reduction in apoptosis, mediated by Akt upregulation and ERK1/2 downregulation, and inhibition of interstitial fibrosis via MMP-9 suppression compared with the STZ group. Oxidative stress was significantly hindered in iPS cell and CM groups as evidenced by diminished pro-oxidant expression and enhanced antioxidant (catalase and MnSOD) concentration. Echocardiography data suggest a significant improvement in cardiac function in cells and CM groups in comparison to STZ. In conclusion, our data strongly suggest that iPS cells and CM attenuate oxidative stress and associated apoptosis and fibrosis. Moreover, we also suggest that increased antioxidant levels, decreased adverse cardiac remodeling, and improved cardiac function is mediated by iPS CM and cells in DICM through multiple autocrine and paracrine mechanisms.