The therapeutic efficacy comparison of MSCs derived different tissues unveilings anti-apoptosis more crucial than angiogenesis in treating acute myocardial infarction

Abstract

Background Myocardial infarction (MI) is a severe disease that often associated with impaired angiogenesis and increased myocardial apoptosis. Mesenchymal stromal cells (MSCs) have been a promising candidate for treating myocardial infarction. However, functional heterogeneity of MSCs leads to inconsistent therapeutic efficiency and the current MSCs-based therapy lacks the concept and implementation of precision medicine. In this study, we compared the cardioprotective effect of UCMSCs and ADMSCs targeting the angiogenesis in a mouse MI model and screened out optimum MSCs candidate for precise clinical application. Methods The gene expression profiles of UCMSCs and ADMSCs were investigated through RNA sequencing analysis. To compare their angiogenic potential, we performed tube formation assay, Matrigel plug assays, and aortic ring assay, and analyzed pro-angiogenic genes via qPCR. Subsequently, UCMSCs and ADMSCs were respectively injected into myocardium after MI surgery in mice. On day 28 post-MI, echocardiography was performed to assess cardiac function. Histological analysis was performed to assess MSCs retention, angiogenesis, and myocardial apoptosis. Additionally, the anti-apoptosis effects mediated by MSCs were further evaluated using flow cytometry in hypoxia H9C2 and HL-1 cells. Results The RNA sequencing analysis revealed differences in gene expression related to angiogenesis and apoptosis pathways between UCMSCs and ADMSCs. UCMSCs presented greater pro-angiogenesis activity than ADMSCs in vitro and in vivo. Both of UCMSCs and ADMSCs improved cardiac function, decreased infarction area and inhibited cardiomyocyte apoptosis while promoting angiogenesis post-MI in mice. Notably, ADMSCs exerted a better cardioprotective function than UCMSCs and stronger anti-apoptotic effect on residual cardiomyocytes.

1. Introduction

Myocardial infarction (MI) is a leading cause of death worldwide caused by the occlusion of blood flow in the cardiac coronary arteries. Restricted blood supply causes irreversible loss of cardiomyocytes, which eventually leads to severely impaired cardiac function, resulting in a significant decrease in quality of life, and increased mortality. Myocardial repair and regeneration has always been a heated and difficult topic in medical research. After a heart attack, a complex series of repair and regeneration processes are triggered to restore myocardial function, involving inflammatory responses, apoptosis and angiogenesis. Among them, angiogenesis is the pivotal process of myocardial repair after myocardial injury, which is crucial for restoring blood supply and promoting the survival and regeneration of cardiomyocytes [1–4].

Cardiomyocytes will be necrotic due to ischemia and hypoxia, which results from interrupted or reduced blood flow within the heart caused by a blockage in the coronary artery. The formation of new blood vessels facilitates the survival and regeneration of cardiomyocytes following ischemic injury by conferring better perfusion to the myocardium. Neovascularization is a process of developing new vascular networks, primarily mediated by the proliferation, migration, and differentiation of vascular endothelial cells (ECs), which is augmented by various growth factors, cytokines and hormones, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Therefore, angiogenesis is vital for promoting reperfusion and functional recovery of ischemic heart and the induction of cardiac angiogenesis has become one of the key strategies in MI treatment [5–6].