Extracellular Vesicle-Derived microRNAs of Human Wharton’s Jelly Mesenchymal Stromal Cells May Activate Endogenous VEGF-A to Promote Angiogenesis |
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Authors: | Cinzia Maria Chinnici Gioacchin Iannolo Ettore Cittadini Anna Paola Carreca David Nascari Francesca Timoneri Mariangela Di Bella Nicola Cuscino Giandomenico Amico Claudia Carcione Pier Giulio Conaldi |
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Affiliation: | 1.Fondazione Ri.MED, Regenerative Medicine and Biomedical Technologies Unit, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (A.P.C.); (F.T.); (M.D.B.); (G.A.); (C.C.);2.Department of Research, IRCCS-ISMETT, 90127 Palermo, Italy; (G.I.); (N.C.); (P.G.C.);3.Casa di Cura Candela, 90141 Palermo, Italy;4.McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; |
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Abstract: | Despite low levels of vascular endothelial growth factor (VEGF)-A, the secretome of human Wharton’s jelly (WJ) mesenchymal stromal cells (MSCs) effectively promoted proangiogenic responses in vitro, which were impaired upon the depletion of small (~140 nm) extracellular vesicles (EVs). The isolated EVs shared the low VEGF-A profile of the secretome and expressed five microRNAs, which were upregulated compared to fetal dermal MSC-derived EVs. These upregulated microRNAs exclusively targeted the VEGF-A gene within 54 Gene Ontology (GO) biological processes, 18 of which are associated with angiogenesis. Moreover, 15 microRNAs of WJ-MSC-derived EVs were highly expressed (Ct value ≤ 26) and exclusively targeted the thrombospondin 1 (THBS1) gene within 75 GO biological processes, 30 of which are associated with the regulation of tissue repair. The relationship between predicted microRNA target genes and WJ-MSC-derived EVs was shown by treating human umbilical-vein endothelial cells (HUVECs) with appropriate doses of EVs. The exposure of HUVECs to EVs for 72 h significantly enhanced the release of VEGF-A and THBS1 protein expression compared to untreated control cells. Finally, WJ-MSC-derived EVs stimulated in vitro tube formation along with the migration and proliferation of HUVECs. Our findings can contribute to a better understanding of the molecular mechanisms underlying the proangiogenic responses induced by human umbilical cord-derived MSCs, suggesting a key regulatory role for microRNAs delivered by EVs. |
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Keywords: | Wharton’ s jelly mesenchymal stromal cells extracellular vesicles microRNAs VEGF-A and THBS1 target genes in vitro angiogenesis |
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