Extracellular vesicles enriched with an endothelial cell pro-survival microRNA affects skin tissue regeneration

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 capabl...

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Bibliographic Details
Published in:	Molecular therapy. Nucleic acids Vol. 28; pp. 307 - 327
Main Authors:	Fernandes, Hugo, Zonnari, Alessandra, Abreu, Ricardo, Aday, Sezin, Barão, Marta, Albino, Inês, Lino, Miguel, Branco, Ana, Seabra, Cátia, Barata, Tânia, Leal, Ermelindo C., Tralhão, José Guilherme, Gonçalves, Lino, de Jong, Alwin, Peters, Hendrika A.B., de Vries, Margreet R., da Costa Martins, Paula, Quax, Paul H.A., Ferreira, Lino
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 14-06-2022 American Society of Gene & Cell Therapy Elsevier
Subjects:	angiogenesis endothelial cells extracellular vesicles high-throughput screening microRNAs non-coding RNAs Original pro-survival wound healing microRNAs endothelial cells wound healing extracellular vesicles non-coding RNAs angiogenesis pro-survival high-throughput screening
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Summary:	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. [Display omitted] Tissue regeneration is a well-orchestrated process often impaired due to aging and/or chronic diseases such as diabetes. Using high-throughput screening and libraries of miRNAs, we identified novel miRNAs capable of improving cell survival and ultimately regeneration. Additionally, we developed an extracellular vesicle-based formulation to deliver in vivo the selected miRNA.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2162-2531 2162-2531
DOI:	10.1016/j.omtn.2022.03.018