miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury

Basic Res Cardiol. 2021 Mar 19;116(1):19. doi: 10.1007/s00395-021-00858-8.

Abstract

Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

Keywords: Cell cycle re-entry; EVs; Endogenous cardiac repair mechanism; IPSCs; MiRNAs; Myocardial Infarction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line
  • Cell Proliferation*
  • Disease Models, Animal
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / transplantation*
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / surgery*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Receptor, Notch3 / genetics
  • Receptor, Notch3 / metabolism*
  • Recovery of Function
  • Regeneration*
  • Signal Transduction
  • Ventricular Function, Left

Substances

  • MIRN106 microRNA, human
  • MicroRNAs
  • Notch3 protein, mouse
  • Receptor, Notch3