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

Research output: Contribution to journalArticle

  • 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
Original languageEnglish
Pages (from-to)1694-1705
Number of pages12
JournalMolecular Therapy
Volume26
Issue number7
Early online date15 Jun 2018
DOIs
DateAccepted/In press - 5 Jun 2018
DateE-pub ahead of print - 15 Jun 2018
DatePublished (current) - 5 Jul 2018

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.

    Research areas

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

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S1525001618302624 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 232 KB, PDF-document

    Licence: CC BY-NC-ND

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