miRNAs in Extracellular Vesicles from iPS-Derived Cardiac Progenitor Cells Effectively Reduce Fibrosis and Promote Angiogenesis in Infarcted Heart

Abstract

Cardiac stem cell therapy offers the potential to ameliorate postinfarction remodeling and development of heart failure but requires optimization of cell-based approaches. Cardiac progenitor cells (CPCs) induction by ISX-9, a small molecule possessing antioxidant, prosurvival, and regenerative properties, represents an attractive potential approach for cell-based cardiac regenerative therapy. Here, we report that extracellular vesicles (EV) secreted by ISX-9-induced CPCs (EV-CPCISX-9) faithfully recapitulate the beneficial effects of their parent CPCs with regard to postinfarction remodeling. These EV contain a distinct repertoire of biologically active miRNAs that promoted angiogenesis and proliferation of cardiomyocytes while ameliorating fibrosis in the infarcted heart. Amongst the highly enriched miRNAs, miR-373 was strongly antifibrotic, targeting 2 key fibrogenic genes, GDF-11 and ROCK-2. miR-373 mimic itself was highly efficacious in preventing scar formation in the infarcted myocardium. Together, these novel findings have important implications with regard to prevention of postinfarction remodeling.

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Another strategy that has been lately pursued focusses on iPS cells as an exploitable "biopharmaceutical" source of (cardiovascular) progenitor cells and cardiomyocytes [168]. Indeed, multipotent CPCs have been generated from human iPS cells via stimulation of the small antioxidant molecule ISX-9; extracellular vesicles secreted by ISX-9-induced CPCs (EV-CPC ISX-9 ) counteracted cardiac fibrosis and ameliorated local angiogenesis in mice undergoing MI putatively via antifibrotic miR-373 delivery [169]. Similarly, iPS cell-derived cardiomyocytes (iCMs) have been broadly described as an alternative option for cell therapy approach [170]; since rodent cardiomyocytes have shown to secrete EVs biologically active on cardiovascular cells, iCM-EVs may offer an abundant paracrine source as well.…”

Human iPS Cells Derived Skeletal Muscle Progenitor Cells Promote Myoangiogenesis and Restore Dystrophin in Duchenne Muscular Dystrophic Mice

“…EV were isolated using size exclusion column method as we described previously (16). Briefly, conditioned media was collected and EV were isolated by centrifugation at 3000 rpm for 30 min to remove cells and debris, followed by filtration through a 0.22 μm filter to remove the remaining debris.…”

“…Particle size and concentration were analyzed using tunable resistive pulse sensing (TRPS) technique with a qNano instrument (Izon Science) as described in previous studies (16,17). Briefly, the number of particles were counted (at least 600 to 1000 events) at 20 mbar pressure.…”

“…Tissue samples were processed for TEM by the Electron Microscopy and Histology Core Laboratory at Augusta University as described previously (16). Briefly, EV suspension was fixed with an equal volume of 8% paraformaldehyde to preserve ultrastructure.…”

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

“…EV cytoprotective effect is also related to their miRNA content, in particular miRNA-21 and miRNA-210. Xuan et al generated cardiac progenitor cells (CPCs) starting from iPSCs by treating them with the small molecule ISX-9, with antioxidant and regenerative properties, and used EVs derived from these cells to repair post-infarcted heart [199]. They found that the cardioprotective EV effect was in part due to their miRNA content.…”