TY - JOUR
T1 - Extracellular vesicles enriched with an endothelial cell pro-survival microRNA affects skin tissue regeneration
AU - Fernandes, Hugo
AU - Zonnari, Alessandra
AU - Abreu, Ricardo
AU - Aday, Sezin
AU - Barão, Marta
AU - Albino, Inês
AU - Lino, Miguel
AU - Branco, Ana
AU - Seabra, Cátia
AU - Barata, Tânia
AU - Leal, Ermelindo C
AU - Tralhão, José Guilherme
AU - Gonçalves, Lino
AU - de Jong, Alwin
AU - Peters, Hendrika A B
AU - de Vries, Margreet R
AU - da Costa Martins, Paula
AU - Quax, Paul H A
AU - Ferreira, Lino
N1 - © 2022 The Authors.
PY - 2022/6/14
Y1 - 2022/6/14
N2 - 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.
AB - 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.
KW - THERAPEUTIC ANGIOGENESIS
KW - VASCULAR COMPLICATIONS
KW - ISCHEMIC DISEASE
KW - GROWTH-FACTOR
KW - STEM-CELLS
KW - NEOVASCULARIZATION
KW - VASCULOGENESIS
KW - EXPRESSION
KW - RECOVERY
KW - PROMOTE
U2 - 10.1016/j.omtn.2022.03.018
DO - 10.1016/j.omtn.2022.03.018
M3 - Article
C2 - 35474734
SN - 2162-2531
VL - 28
SP - 307
EP - 327
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
ER -