Activated Stat5 trafficking Via Endothelial Cell-derived Extracellular Vesicles Controls IL-3 Pro-angiogenic Paracrine Action

Soluble factors and cell-derived extracellular vesicles (EVs) control vascular cell fate during inflammation. The present study investigates the impact of Interleukin 3 (IL-3) on EV release by endothelial cells (ECs), the mechanisms involved in EV release and paracrine actions. We found that IL-3 in...

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Bibliographic Details
Published in:Scientific reports 2016-05, Vol.6 (1), p.25689-25689, Article 25689
Main Authors: Lombardo, Giusy, Dentelli, Patrizia, Togliatto, Gabriele, Rosso, Arturo, Gili, Maddalena, Gallo, Sara, Deregibus, Maria Chiara, Camussi, Giovanni, Brizzi, Maria Felice
Format: Article
Language:English
Subjects:
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Angiogenesis
Cell fate
Chromatin
Cyclin D1
Endothelial cells
Extracellular vesicles
Humanities and Social Sciences
Immunoprecipitation
Interleukin 3
multidisciplinary
Paracrine signalling
Science
Signal transduction
Stat5 protein
Transcription
Wound healing
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Summary:Soluble factors and cell-derived extracellular vesicles (EVs) control vascular cell fate during inflammation. The present study investigates the impact of Interleukin 3 (IL-3) on EV release by endothelial cells (ECs), the mechanisms involved in EV release and paracrine actions. We found that IL-3 increases EV release, which is prevented by IL-3Ralpha blockade. EVs released upon IL-3 stimulation were able to induce pro-angiogenic signals as shown by chromatin immunoprecipitation (ChIP) assay performed on the promoter region of cyclin D1 and tridimensional tube-like structure formation. We herein demonstrate that these effects rely on the transfer of miR-126-3p, pre-miR-126 and, more importantly, of activated signal transduction and activator of transcription 5 (pSTAT5) from IL-3-EV cargo into recipient ECs. We show, using the dominant negative form (ΔN)STAT5 and an activated STAT5 (1*6STAT5) constructs, that STAT5 drives IL-3-mediated EV release, miR-126-3p and pSTAT5 content. Finally, using EVs recovered from ΔNSTAT5 expressing ECs, we provide evidence that miR-126-3p and pSTAT5 trafficking is relevant for IL-3-mediated paracrine pro-angiogenic signals. These results indicate that IL-3 regulates EC-EV release, cargo and IL-3 angiogenic paracrine action via STAT5. Moreover, these results provide evidence that EC-derived IL-3-EVs can serve as pro-angiogenic clinical delivery wound healing devices.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep25689