MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart

Int J Mol Sci. 2016 Oct 20;17(10):1752. doi: 10.3390/ijms17101752.

Abstract

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy.

Keywords: adipose-derived stem cell (ASC); apoptosis signal-regulating kinase 1 (ASK1); mesenchymal stem cells (MSCs); microRNA-301a; myocardial infarction (MI); reactive oxygen species (ROS).

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Cell Line
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Humans
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / cytology*
  • MicroRNAs / genetics*
  • Myocardial Infarction
  • Oxidative Stress / physiology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rats
  • Reactive Oxygen Species / metabolism

Substances

  • MIRN301 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human