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

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          Abstract

          <p class="first" id="d8824108e310">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. <i>In vivo</i>, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. <i>In vitro</i>, 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, <i>ex-vivo</i> 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. </p><p class="first" id="d8824108e322">MicroRNA (miR) modulation to potentiate the functionality vascular regenerative cells may represent a successful strategy to optimize cell therapies for ischemic diseases. Spinetti, Martelli, Emanueli, et al. here demonstrate that the master hypoxamiR miR-210 improves human circulating proangiogenic cells functions and their therapeutic potential in limb ischemia. </p>

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          Author and article information

          Journal
          Molecular Therapy
          Molecular Therapy
          Elsevier BV
          15250016
          July 2018
          July 2018
          : 26
          : 7
          : 1694-1705
          Article
          10.1016/j.ymthe.2018.06.003
          6036333
          29908843
          4e5edd8b-3da0-4c64-ac3d-542e467e544a
          © 2018

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