Embryonic Stem Cell–Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction

Abstract

Rationale Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to various concerns. Recently, salutary effects of stem cells have been connected to exosome secretion. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective Determine the effect of ESC-derived exosome for the repair of ischemic myocardium and whether c-kit+ CPCs function can be enhanced with ESC exosomes Methods and Results This study demonstrates that mouse ESC derived exosomes (mES Ex) possess ability to augment function in infarcted hearts. mES Ex enhanced neovascularization, cardiomyocyte survival and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex augmented cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 8 weeks after in vivo transfer along with formation of bonafide new cardiomyocytes in the ischemic heart. miRNA array revealed significant enrichment of miR290–295 cluster and particularly miR-294 in ESC exosomes. The underlying basis for the beneficial effect of mES Ex was tied to delivery of ESC specific miR-294 to CPCs promoting increased survival, cell cycle progression and proliferation. Conclusions mES Ex provide a novel cell free system that utilizes the immense regenerative power of ES cells while avoiding the risks associated with direct ES or ES derived cell transplantation and risk of teratomas. ESC exosomes possess cardiac regeneration ability and modulate both cardiomyocyte and CPC based repair programs in the heart.

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

“…Stem cells with enhanced paracrine signaling should be able to augment cardiac repair mitigating direct protection 36 on the existing myocyte or stimulating the endogenous pool of stem cells to replicate and contribute in repair processes. 37 After lineage commitment, all 3 stem cell types expressed paracrine factors known to be responsible for improvements in cardiac function after stem cell transplantation (Figure 3). In our previous published findings, we have shown that, after 24 hours and 2 weeks of CBSCs transplantation, levels of paracrine factors including bFGF and VEGF are upregulated 1 and could account for enhanced neovascularization previously observed in CBSCs-injected animals after ischemic insult.…”

Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury

“…In the past few years, multiple studies have focused on the protective effects of stem cell-derived exogenous EVs against cardiomyocyte apoptosis in the ischemic myocardium [3, 28, 44, 47]. Interestingly, it was recently reported that endogenous plasma EVs could also protect the heart from ischemia-reperfusion (I/R) injury, providing compelling evidence that circulating EVs are able to deliver endogenous protective signals to the heart even in a physiological condition [46].…”

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

“…Khan et al (69) addressed the effect of mouse ESC-derived exosomes for the repair of ischemic myocardium and whether c-kit + CPC function can be enhanced with these vesicles. ESC exosomes enhanced neovascularization, CPC survival, proliferation and cardiac commitment, along with an increase in cardiac function and a decrease in fibrosis post-MI.…”