MicroRNA-145 Regulates the Differentiation of Adipose Stem Cells Toward Microvascular Endothelial Cells and Promotes Angiogenesis
Por:
Arderiu, G, Pena, E, Aledo, R, Juan-Babot, O, Crespo, J, Vilahur, G, Onate, B, Moscatiello, F, Badimon, L
Publicada:
21 jun 2019
Resumen:
Rationale: Adipose-derived stem cells (ASCs) are a potential adult mesenchymal stem cell source for restoring endothelial function in ischemic tissues. However, the mechanism that promotes ASCs differentiation toward endothelial cells (ECs) is not known. Objective: To investigate the mechanisms of ASCs differentiation into ECs. Methods and Results: ASCs were isolated from clinical lipoaspirates and cultured with DMEM or endothelial cell-conditioned medium. Endothelial cell-conditioned medium induced downregulation of miR-145 in ASCs and promoted endothelial differentiation. We identified bFGF (basic fibroblast growth factor) released by ECs as inducer of ASCs differentiation through receptor-induced AKT (protein kinase B) signaling and phosphorylation of FOXO1 (forkhead box protein O1) suppressing its transcriptional activity and decreasing miR-145 expression. Blocking bFGF-receptor or PI3K/AKT signaling in ASCs increased miR-145 levels. Modulation of miR-145 in ASCs, using a miR-145 inhibitor, regulated their differentiation into ECs: increasing proliferation, migration, inducing expression of EC markers (VE-cadherin, VEGFR2 [vascular endothelial growth factor receptor 2], or VWF [von Willebrand Factor]), and tube-like formation. Furthermore, in vivo, downregulation of miR-145 in ASCs enhanced angiogenesis in subcutaneously implanted plugs in mice. In a murine hindlimb ischemia model injection of ASCs with downregulated miR-145 induced collateral flow and capillary formation evidenced by magnetic resonance angiography. Next, we identified ETS1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1) as the target of miR-145. Upregulation of miR-145 in ASCs, by mimic miR-145, suppressed ETS1 expression and consequently abolished EC differentiation and the angiogenic properties of endothelial cell-conditioned medium-preconditioned ASCs; whereas, overexpression of ETS1 reversed the abrogated antiangiogenic capacity of miR-145. ETS1 overexpression induced similar results to those obtained with miR-145 knockdown. Conclusions: bFGF released by ECs induces ASCs differentiation toward ECs through miR-145-regulated expression of ETS1. Downregulation of miR-145 in ASCs induce vascular network formation in ischemic muscle.
Filiaciones:
Arderiu, G:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Pena, E:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
Aledo, R:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
Juan-Babot, O:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Crespo, J:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Vilahur, G:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
Onate, B:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Moscatiello, F:
Clin Teknon, Barcelona, Spain
Badimon, L:
IR Hosp Santa Creu & St Pau, IIBSantPau, Cardiovasc Program ICCC, Barcelona, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
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