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

Wanling Xuan,Muhammad Ashraf,Meifeng Xu,Lei Wang,Neal L Weintraub

doi:10.1155/2019/3726392

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.

Highlights

Myocardial infarction (MI) and subsequent heart failure are a leading cause of death worldwide [1]
For Cardiac progenitor cells (CPCs) generation, briefly, human-induced pluripotent stem cells (hiPSCs) maintained on vitronectin-coated six-well plates in mTeSR1 media (Stem Cell Technology) were dissociated into single cells using Accutase (Invitrogen) at 37°C for 10 min and were seeded on to vitronectin-coated six-well plates at 1 × 106 cells/well in mTeSR1 supplemented with 5 μM ROCK inhibitor (Y-27632, Stem Cell Technology) for 24 h
The miR-373 mimic promoted angiogenesis, which was likely mediated by its ability to activate HIF downstream signaling [39]. These findings suggest that the antifibrotic effects of extracellular vesicles (EV)-CPCISX-9 are, at least in part, mediated by miR-373, and they support the notion that the miR373 mimic might represent a novel therapeutic strategy for controlling fibrosis and cardiac remodeling post infarction and perhaps in other disorders, such as diabetic cardiomyopathy

Summary

Introduction

Myocardial infarction (MI) and subsequent heart failure are a leading cause of death worldwide [1]. Despite advances in medical and device therapies, heart failure continues to be associated with a 5-year mortality of ~50%. Stem cell therapy offers a great potential for cardiac tissue repair and regeneration, which might improve symptoms and longevity [2]. The beneficial effects of cardiac stem cell therapy are largely attributed to a paracrine mechanism of action that involves the release of cellular factors from the transplanted stem cells [3,4,5]. Cardiac progenitor cells (CPCs) are of particular interest due to their inherent properties of cell protection, cell development, differentiation, and desirable effects imparted into the host tissue [8,9,10]. EV secreted from young cardiosphere-derived cells exerted stronger antisenescent effects than those derived from aged animals [12]

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