Role of Mir-155 in Controlling HIF-1α Level and Promoting Endothelial Cell Maturation

Sci Rep. 2016 Oct 12:6:35316. doi: 10.1038/srep35316.

Abstract

Stem-cell-based therapy for cardiovascular disease, especially ischemic heart disease (IHD), is a promising approach to facilitating neovascularization through the migration of stem cells to the ischemic site and their subsequent differentiation into endothelial cells (ECs). Hypoxia is a chief feature of IHD and the stem cell niche. However, whether hypoxia promotes stem cell differentiation into ECs or causes them to retain their stemness is controversial. Here, the differentiation of pluripotent stem cells (iPSCs) into endothelial cells (ECs) was induced under hypoxia. Though the angiogenic capability and angiogenesis-related autocrine/paracrine factors of the ECs were improved under hypoxia, the level of hypoxia inducible factor 1α (HIF-1α) was nonetheless found to be restricted along with the EC differentiation. The down-regulation of HIF-1α was found to have been caused by VEGF-induced microRNA-155 (miR-155). Moreover, miR-155 was also found to enhance the angiogenic capability of induced ECs by targeting E2F2 transcription factor. Hence, miR-155 not only contributes to controlling HIF-1α expression under hypoxia but also promotes angiogenesis, which is a key feature of mature ECs. Revealing the real role of hypoxia and clarifying the function of miR-155 in EC differentiation may facilitate improvement of angiogenic gene- and stem-cell-based therapies for ischemic heart disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Hypoxia
  • Cell Line
  • E2F2 Transcription Factor / genetics*
  • E2F2 Transcription Factor / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Feeder Cells
  • Fibroblasts / cytology
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neovascularization, Physiologic / genetics
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • E2F2 Transcription Factor
  • E2F2 protein, human
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN155 microRNA, human
  • MicroRNAs
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A