Systemic administration of hEPSC-derived Trophoblast stem cells for cardiac regeneration

Abstract Background Myocardial infarction (MI) is the leading cause of death all over the world. The limited regeneration capacity of adult mammal heart leads to irreversible cardiomyocytes damages, causing pathological left ventricular remodeling and heart failure (HF). Recent studies have demonstrated that placenta derived caudal-type homeobox-2 (CDX2) positive cells could engraft in injured heart, and differentiate into functional cardiomyocyte and endothelial cells to improve cardiac function after MI. However, these cells are isolated from end-gestation placentas and could not be mass-produced. CDX2 is the master homeodomain protein that defines trophectoderm during development and is further involved in self-renewal of trophoblast stem cells that finally form placenta. Purpose To investigate the safety and therapeutic potential of trophoblast stem cells (TSCs) derived from human expanded potential stem cells (hEPSCs) in a mouse model of MI. Methods Mice were randomized into 2 groups to undergo intravenous administration of PBS (MI group) and hTSCs (hTSCs group) respectively following MI, which was induced by ligation of the left anterior descending coronary artery. Echocardiography was performed to evaluate the cardiac function. Masson Trichrome and immunofluorescence staining were performed to investigate the potential mechanisms. Results In this study, we successfully generated TSC from hEPSCs. Echocardiography showed that left ventricle ejection fraction (LVEF) increased significantly in hTSCs group compared with MI group 4 weeks after cell transplantation. Masson staining showed that the infarct size in hTSCs group significantly decreased compared with MI group. Meanwhile, immunofluorescence staining with α-smooth muscle actin (α-SMA) and Ki67 showed that hTSCs could increase microvascular density and improve cell proliferation. Conclusion Trophoblast stem cells derived from hEPSCs could enhance cardiac function after MI through mechanisms involving neovascularization, anti-fibrosis and cell proliferation. Our findings provide important insight into the development of a new therapeutic approach to heart regeneration after MI.