Transplantation of telomerase/myocardin-co-expressing mesenchymal cells in the mouse promotes myocardial revascularization and tissue repair

Vascul Pharmacol. 2020 Dec;135:106807. doi: 10.1016/j.vph.2020.106807. Epub 2020 Oct 31.

Abstract

Aim: Cell therapies are hampered by poor survival and growth of grafts. We tested whether forced co-expression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD) improves post-infarct revascularization and tissue repair by adipose tissue-derived mesenchymal stromal cells (AT-MSCs).

Methods and results: We transplanted AT-MSCs overexpressing MYOCD and TERT in a murine model of acute myocardial infarction (AMI). We characterized paracrine effects of AT-MSCs. When transplanted into infarcted hearts of C57BL/6 mice, AT-MSCs overexpressing TERT and MYOCD decreased scar tissue and the intra-scar CD3 and B220 lymphocyte infiltration; and increased arteriolar density as well as ejection fraction compared with saline or mock-transduced AT-MSCs. These effects were accompanied by higher persistence of the injected cells in the heart, increased numbers of Ki-67+ and CD117+ cells, and the expression of cardiac actin and β-myosin heavy chain. Intramyocardial delivery of the secretome and its extracellular vesicle (EV)-enriched fraction also decreased scar tissue formation and increased arteriolar density in the murine AMI model. Proteomic analysis of AT-MSCs-EV-enriched fraction predicted the activation of vascular development and the inhibition of immune cell trafficking. Elevated concentrations of miR-320a, miR-150-5p and miR-126-3p associated with regulation of apoptosis and vasculogenesis were confirmed in the AT-MSCs-EV-enriched fraction.

Conclusions: AT-MSCs overexpressing TERT and MYOCD promote persistence of transplanted aged AT-MSCs and enhance arteriolar density in a murine model of AMI. EV-enriched fraction is the component of the paracrine secretion by AT-MSCs with pro-angiogenic and anti-fibrotic activities.

Keywords: Adipose tissue–derived mesenchymal stromal cells; Extracellular vesicles; Myocardial infarction; Myocardin; Telomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / genetics
  • Angiogenic Proteins / metabolism
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Extracellular Vesicles / enzymology
  • Extracellular Vesicles / transplantation
  • Fibrosis
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / enzymology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / surgery*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Paracrine Communication
  • Recovery of Function
  • Regeneration*
  • Signal Transduction
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • Angiogenic Proteins
  • MicroRNAs
  • Nuclear Proteins
  • Trans-Activators
  • myocardin
  • Green Fluorescent Proteins
  • TERT protein, human
  • Telomerase