miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia

Marie Besnier, Stefano Gasparino, Rosa Vono, Elena Sangalli, Amanda Facoetti, Valentina Bollati, Laura Cantone, Germana Zaccagnini, Biagina Maimone, Paola Fuschi, Daniel Da Silva, Michele Schiavulli, Sezin Aday, Massimo Caputo, Paolo Madeddu, Costanza Emanueli, Fabio Martelli, Gaia Spinetti

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.

Original languageEnglish
Pages (from-to)1694-1705
Number of pages12
JournalMolecular Therapy
Volume26
Issue number7
Early online date15 Jun 2018
DOIs
Publication statusPublished - 5 Jul 2018

Keywords

  • microRNA-210
  • EFNA3
  • bone-marrow-derived circulating cells
  • angiogenesis
  • limb ischemia
  • cell therapy

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