<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
actions of transplanted PACs.
<i>In vitro</i>, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and
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.
<i>ex-vivo</i> pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic
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.