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Title: Extracellular vesicles enriched with an endothelial cell pro-survival microRNA affects skin tissue regeneration
Authors: Fernandes, Hugo 
Zonnari, Alessandra
Abreu, Ricardo Cerqueira de 
Aday, Sezin
Barão, Marta 
Albino, Inês 
Lino, Miguel 
Branco, Ana
Seabra, Cátia 
Barata, Tânia
Leal, Ermelindo C. 
Tralhão, José Guilherme
Gonçalves, Lino 
Jong, Alwin de
Peters, Hendrika A.B.
de Vries, Margreet R.
Martins, Paula da Costa 
Quax, Paul H.A.
Ferreira, Lino 
Keywords: angiogenesis; endothelial cells; extracellular vesicles; high-throughput screening; microRNAs; non-coding RNAs; pro-survival; wound healing
Issue Date: 2022
Publisher: Elsevier
Project: info:eu-repo/grantAgreement/EC/H2020/669088/EU/Enhancing Research in Ageing at the University of Coimbra 
info:eu-repo/grantAgreement/EC/H2020/952266/EU/RESEarch for healThy AGEING 
Serial title, monograph or event: Molecular Therapy - Nucleic Acids
Volume: 28
Abstract: Endothelial cell (EC) activity is essential for tissue regeneration in several (patho)physiological contexts. However, our capacity to deliver in vivo biomolecules capable of controlling EC fate is relatively limited. Here, we screened a library of microRNA (miR) mimics and identified 25 miRs capable of enhancing the survival of ECs exposed to ischemia-mimicking conditions. In vitro, we showed that miR-425-5p, one of the hits, was able to enhance EC survival and migration. In vivo, using a mouse Matrigel plug assay, we showed that ECs transfected with miR-425-5p displayed enhanced survival compared with scramble-transfected ECs. Mechanistically, we showed that miR-425-5p modulated the PTEN/PI3K/AKT pathway and inhibition of miR-425-5p target genes (DACH1, PTEN, RGS5, and VASH1) phenocopied the pro-survival. For the in vivo delivery of miR-425-5p, we modulated small extracellular vesicles (sEVs) with miR-425-5p and showed, in vitro, that miR-425-5p-modulated sEVs were (1) capable of enhancing the survival of ECs exposed to ischemia-mimic conditions, and (2) efficiently internalized by skin cells. Finally, using a streptozotocin-induced diabetic wound healing mouse model, we showed that, compared with miR-scrambled-modulated sEVs, topical administration of miR-425-5p-modulated sEVs significantly enhanced wound healing, a process mediated by enhanced vascularization and skin re-epithelialization. © 2022 The Authors
ISSN: 21622531
DOI: 10.1016/j.omtn.2022.03.018
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais
IIIUC - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais

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