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Towards Effective Stem Cell Treatment of Ischemia

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Review of “MicroRNA-21 coordinates Human Multipotent Cardiovascular Progenitors Therapeutic Potential” from Stem Cells by Stuart P. Atkinson

Current trials of adult stem cells for the treatment of ischemic diseases have demonstrated a modest benefit to patients. However, endogenous cell sources are limited by the fact that cardiovascular risk factors, e.g. age, and disease, impair adult stem cell function. The production of a purified population of multipotent cardiovascular progenitors (SSEA1+MesP1+ MCPs) which generate cardiomyocytes as well as endothelial cells and smooth muscle cells [1] has been described. This cell population could have the ability to promote post‐ischemic revascularization of the hindlimb through both angiogenic and arteriogenic processes to efficiently restore tissue perfusion in the ischemic tissue. The group of Jean-Sébastien Silvestre (PARCC-Inserm, Paris, France), who first identified these cells, now assess this MCPs in an experimental model of critical limb ischemia (CLI) with additional findings on the role of small non‐coding RNAs (miRNAs) in angiogenesis uncovered [2].

The group sorted MCPs from cultures of hESCs treated with BMP2 and Wnt3A [1] and then assessed their therapeutic efficiency after intramuscular injection into nude mice with CLI. All measured scores (foot perfusion, capillary density and arteriole density) improved upon injection of only 1,00 to 10,000 MCPs, this being more effective than administration of mixed endothelial progenitor cells and mesenchymal stem cells; the gold standard for pro‐angiogenic stem cell therapy. Treatment of cells with VEGF-A or PDGF-BB to stimulate the progeny for endothelial or mural (vascular smooth muscle/pericyte) cells, previously linked to improved post‐ischemic revascularization [3, 4], did not however demonstrate any additional benefit over and above transplantation of untreated MCPs.

Previous miRNA analysis of hESC-derived MCPs indicated an important role for miR-21, an miRNA linked to the angiogenic phenotype. miR-21 inhibition inhibited the pro‐angiogenic effect of hESC-derived MCPs through increased apoptosis and decreased engraftment (See Figure), and also reduced paracrine pro‐angiogenic factor expression. Interestingly, ischemic tissue expressed miR-21, peaking at day 3 post onset mainly in infiltrated cells and in the vascular structures of ischemic muscle. Induction of unilateral hindlimb ischemia in miR‐21‐deficient mice led to a defective angiogenic phenotype compared to wild type mice. Further analysis of miR-21 expression in infiltrated cells found high miR-21 expression in CD68+ monocytes/macrophages in the ischemic muscle, blood and bone marrow. Indeed, engraftment of wild type bone marrow in miR‐21 KO mice rescued defective post ischemic revascularization suggesting that miR‐21 regulates bone marrow‐derived monocyte number and pro‐angiogenic properties.

This study, alongside two others, demonstrating the safety [1] and efficacy in humanized mice [5], suggests that SSEA‐1+MesP1+ multipotent cardiovascular progenitors represent an exciting therapeutic option in regenerative cardiovascular medicine. Furthermore, the identification of the miR-21 pathway may allow for the uncovering of potentially druggable targets to further promote post‐ischemic revascularization.

References

  1. Blin G, Nury D, Stefanovic S, et al. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. The Journal of clinical investigation 2010;120:1125-1139.
  2. Richart A, Loyer X, Néri T, et al. MicroRNA-21 coordinates Human Multipotent Cardiovascular Progenitors Therapeutic Potential. Stem Cells 2014;n/a-n/a.
  3. Foubert P, Matrone G, Souttou B, et al. Coadministration of endothelial and smooth muscle progenitor cells enhances the efficiency of proangiogenic cell-based therapy. Circulation research 2008;103:751-760.
  4. Yamahara K, Sone M, Itoh H, et al. Augmentation of neovascularization [corrected] in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells. PLoS One 2008;3:e1666.
  5. Colucci F, Soudais C, Rosmaraki E, et al. Dissecting NK cell development using a novel alymphoid mouse model: investigating the role of the c-abl proto-oncogene in murine NK cell differentiation. Journal of immunology 1999;162:2761-2765.