Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132

Rajesh G Katare, Federica Riu, Kathryn J Mitchell, Miriam N Gubernator, Paola Campagnolo, Yuxin Cui, O Fortunato, E Avolio, D Cesselli, AP Beltrami, Gianni D Angelini, Costanza Emanueli, Paolo R Madeddu

Research output: Contribution to journalArticle (Academic Journal)peer-review

270 Citations (Scopus)

Abstract

RATIONALE: Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown.

OBJECTIVE: We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model.

METHODS AND RESULTS: SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S). Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1(nu/nu) or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor- and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts.

CONCLUSION: SVP transplantation produces long-term improvement of cardiac function through a novel paracrine mechanism involving the secretion of miR-132 and inhibition of its target genes.

Translated title of the contributionTransplantation of Human Pericyte Progenitor Cells Improves the Repair of Infarcted Heart Through Activation of an Angiogenic Program Involving Micro-RNA-132
Original languageEnglish
Pages (from-to)894 - 906
Number of pages13
JournalCirculation Research
Volume109
Issue number8
Early online date25 Aug 2011
DOIs
Publication statusPublished - 30 Sep 2011

Keywords

  • Animals
  • Cells, Cultured
  • Humans
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mice
  • Mice, Nude
  • MicroRNAs
  • Myocardial Infarction
  • Neovascularization, Physiologic
  • Pericytes
  • Rats
  • Stem Cells

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