0221: MicroRNA-21 coordinates human multipotent cardiovascular progenitors therapeutic potential and post-ischemic revascularization

Published clinical trials in patients with ischemic diseases show limited benefit of adult stem cell-based therapy, likely due to their restricted plasticity and commitment towards vascular cell lineage. Here, we have uncovered the potent regenerative ability of MesP1/SSEA-1-expressing cardiovascular progenitors enriched from human embryonic stem cells (hESC). Injection of only 104 hESC-derived SSEA-1+/MesP1+ cells, or their progeny obtained after treatment with VEGF-A or PDGF-BB, was effective enough to enhance post-ischemic revascularization in immunodeficient mice with critical limb ischemia (CLI). However, the rate of incorporation of hESC-derived SSEA-1+/MesP1+ cells and their derivatives in ischemic tissues was modest. Alternatively, these cells possessed a unique miR-21 signature that inhibited PTEN thereby activating HIF-1α and the systemic release of VEGF-A. Targeting Dicer or miR-21 limited cell survival in vivo and inhibited their pro-angiogenic capacities both in the Matrigel model and in mice with CLI. Interestingly, we observed an impaired post-ischemic angiogenesis in miR-21 deficient mice suggesting an unrestricted role of miR-21 in this regenerative environment. Notably, amongst the inflammatory cell population, miR-21 was highly expressed in circulating and infiltrated monocytes where it targeted PTEN/HIF- 1α/VEGF-A signaling. As a result, miR-21 deficient mice displayed an impaired number of infiltrated monocytes and a defective angiogenic phenotype that could be partially restored by retransplantation of bone marrow-derived cells from wildtype littermates. Hence, hESC-derived SSEA-1+/MesP1+ cells progenitor cells are powerful key integrators of therapeutic angiogenesis in ischemic milieu and miR- 21 is instrumental in this process as well as in the orchestration of post-ischemic vessel growth