Extracellular Vesicles Secreted by Human Cardiac Progenitors Are an Effective Alternative to Cell Transplantation for Chronic Heart Failure

Introduction: Extracellular vesicles (EV) seem to mediate the benefits of cell therapy for ischemic heart failure (IHF) but the best cellular source of EV and their mechanism of action remain unresolved. Methods: EV secreted by human induced pluripotent stem cell-derived cardiac progenitors (CPg) were isolated by ultracentrifugation. Myocardial infarction was induced in nude mice (permanent LAD occlusion). Three weeks later, mice with LVEF ≤ 45% received transcutaneous echo-guided injections in the peri-infarct myocardium of CPg (1.4x10 6 , n=17), EV secreted by CPg (same batch) over 48 hr (n=19) or PBS (control, n=17). Six weeks later, hearts were blindly evaluated by echocardiography, histology and gene expression profiling. In parallel, in vitro bio-activity assays were developed to determine if fluorescently labelled EV were internalized in cultured rat cardiomyocytes (CM) and could affect their biology following serum deprivation. CPg and EV miRNA content was also assessed by miR arrays. Results: In contrast to CPg or PBS, EV significantly improved cardiac function, as evidenced by decreased LV volumes (LVESV: -11%, p In vitro, EV were internalized by CM, induced a dose-dependent increase in CM viability and proliferation and partially restored the stress-induced impairment of CM conduction velocity in multielectrode array experiments. Among the 101 most abundant EV-miR, 12 were highly conserved across species, of which 8 targeted pathways similarly endowed with a tissue-repair potential (cell differentiation, survival, proliferation). Conclusions: hiPS-CPg-derived EV are effective in IHF treatment, possibly, in part, through EV-mediated miR transfer fostering endogenous cardiac repair. Their benefits in terms of scale-up and regulation could make them effective substitutes for cell transplantation.