title: MicroRNA-21 coordinates human multipotent cardiovascular progenitors therapeutic potential.
abstract: 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 toward vascular cell lineage. We aim to uncover the potent regenerative ability of MesP1/stage-specific embryonic antigen 1 (SSEA-1)-expressing cardiovascular progenitors enriched from human embryonic stem cells (hESCs). Injection of only 10(4) hESC-derived SSEA-1(+) /MesP1(+) cells, or their progeny obtained after treatment with VEGF-A or PDGF-BB, was effective enough to enhance postischemic 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 phosphotase and tensin homolog (PTEN) thereby activating HIF-1α and the systemic release of VEGF-A. Targeting miR-21 limited cell survival and inhibited their proangiogenic capacities both in the Matrigel model and in mice with CLI. We next assessed the impact of mR-21 in adult angiogenesis-promoting cells. We observed an impaired postischemic angiogenesis in miR-21-deficient mice. Notably, miR-21 was highly expressed in circulating and infiltrated monocytes where it targeted PTEN/HIF-1α/VEGF-A signaling and cell survival. 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 wild-type littermates. 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 the biological activity of adult angiogenesis-promoting cells.
authors: INSERM UMRS 970, Paris Descartes University, Sorbonne Paris Cité, Paris, France.
authors: Adèle
authors: A
authors: Richart
authors: Xavier
authors: X
authors: Loyer
authors: Tui
authors: T
authors: Néri
authors: Kiave
authors: K
authors: Howangyin
authors: Coralie L
authors: CL
authors: Guérin
authors: Anta
authors: A
authors: Ngkelo
authors: Wineke
authors: W
authors: Bakker
authors: Ivana
authors: I
authors: Zlatanova
authors: Marie
authors: M
authors: Rouanet
authors: José
authors: J
authors: Vilar
authors: Bernard
authors: B
authors: Lévy
authors: Marc
authors: M
authors: Rothenberg
authors: Ziad
authors: Z
authors: Mallat
authors: Michel
authors: M
authors: Pucéat
authors: Jean-Sébastien
authors: JS
authors: Silvestre
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002470:Cell Survival / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000378:metabolism*
chemical_list: C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs
keywords: Angiogenesis; Inflammation; Ischemia; MicroRNA; Stem cells