Factors Released from Embryonic Stem Cells Stimulate c-kit-FLK-1^+ve Progenitor Cells and Enhance Neovascularization

Abstract

We examined whether factors released from embryonic stem (ES) cells inhibit cardiac and vascular cell apoptosis and stimulate endogenous progenitor cells that enhance neovascularization with improved cardiac function. We generated and transplanted ES-conditioned medium (CM) in the infarcted heart to examine effects on cardiac and vascular apoptosis, activation of endogenous c-kit and FLK-1 +ve cells, and their role in cardiac neovascularization. TUNEL, caspase-3 activity, immunohistochemistry, H&E, and Masson's trichrome stains were used to determine the effect of transplanted ES-CM on cardiac apoptosis and neovascularization. TUNEL staining and caspase-3 activity confirm significantly ( p < 0.05) reduced apoptosis in MI+ES-CM compared with MI+ cell culture medium. Immunohistochemistry demonstrated increased ( p < 0.05, 53%) c-kit +ve and FLK-1 +ve positive cells, as well as increased ( p < 0.05, 67%) differentiated CD31-positive cells in ES-CM groups compared with respective controls. Furthermore, significantly ( p < 0.05) increased coronary artery vessels were observed in ES-CM transplanted hearts compared with control. Heart function was significantly improved following ES-CM transplantation. Next, we observed significantly increased ( p < 0.05) levels of c-kit activation proteins (HGF and IGF-1), anti-apoptosis factors (IGF-1 and total antioxidants), and neovascularization protein (VEGF). In conclusion, we suggest that ES-CM following transplantation in the infarcted heart inhibits apoptosis, activates cardiac endogenous c-kit and FLK-1 +ve cells, and differentiates them into endothelial cells (ECs) that enhances neovascularization with improved cardiac function.

Hypoxia-Pretreated Human MSCs Attenuate Acute Kidney Injury through Enhanced Angiogenic and Antioxidative Capacities

“…It has been demonstrated that factors released from stem cells could significantly scavenge superoxides in ischemic tissues [14]. Therefore, the superoxide levels were determined 24 h after MSC transplantation.…”

Generation of electrophysiologically functional cardiomyocytes from mouse induced pluripotent stem cells

“…[35]. However, the results were more diverse among different iPS cell lines than ES cells, despite the fact that iPS cells closely resemble ES cells in morphology and developmental potential [13,30].…”

Local activation of cardiac stem cells for post‐myocardial infarction cardiac repair

“…The heart has an endogenous reserve of CSCs possessing growth factor receptor systems, when activated with growth factors or stem cell-conditioned medium enriched with growth factors, these cells are able to reconstitute dead myocardial tissue and recover cardiac function [16,20,44,91–93]. Soluble factors released in the pericardial fluids following myocardial necrosis may play a role in the process of the reactivation of an embryonic program in epicardial c-kit POS cells [94], further supporting that activating resident CSCs by growth factors is of great feasibility.…”