Stem Cell-Derived, microRNA-Carrying Extracellular Vesicles: A Novel Approach to Interfering with Mesangial Cell Collagen Production in a Hyperglycaemic Setting.
Extracellular vesicles (EVs) that are derived from stem cells are proving to be promising therapeutic options. We herein investigate the therapeutic potential of EVs that have been derived from different stem cell sources, bone-marrow (MSC) and human liver (HLSC), on mesangial cells (MCs) exposed to hyperglycaemia. By expressing a dominant negative STAT5 construct (ΔNSTAT5) in HG-cultured MCs, we have demonstrated that miR-21 expression is under the control of STAT5, which translates into Transforming Growth Factor beta (TGFβ) expression and collagen production. A number of approaches have been used to show that both MSC- and HLSC-derived EVs protect MCs from HG-induced damage via the transfer of miR-222. This resulted in STAT5 down-regulation and a decrease in miR-21 content, TGFβ expression and matrix protein synthesis within MCs. Moreover, we demonstrate that changes in the balance between miR-21 and miR-100 in the recipient cell, which are caused by the transfer of EV cargo, further contribute to providing beneficial effects. Interestingly, these effects were only detected in HG-cultured cells. Finally, it was found that HG reduced the expression of the nuclear encoded mitochondrial electron transport chain (ETC) components, CoxIV. It is worth noting that EV administration can rescue CoxIV expression in HG-cultured MCs. These results thus demonstrate that both MSC- and HLSC-derived EVs transfer the machinery needed to preserve MCs from HG-mediated damage. This occurs via the horizontal transfer of functional miR-222 which directly interferes with damaging cues. Moreover, our data indicate that the release of EV cargo into recipient cells provides additional therapeutic advantages against harmful mitochondrial signals.
Department of Medical Sciences, University of Turin, Turin, Italy.
Sara
S
Gallo
Department of Medical Sciences, University of Turin, Turin, Italy.
Maddalena
M
Gili
Department of Medical Sciences, University of Turin, Turin, Italy.
Giusy
G
Lombardo
Department of Medical Sciences, University of Turin, Turin, Italy.
Alberto
A
Rossetti
Department of Medical Sciences, University of Turin, Turin, Italy.
Arturo
A
Rosso
Department of Medical Sciences, University of Turin, Turin, Italy.
Patrizia
P
Dentelli
Department of Medical Sciences, University of Turin, Turin, Italy.
Gabriele
G
Togliatto
Department of Medical Sciences, University of Turin, Turin, Italy.
Maria Chiara
MC
Deregibus
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Daniela
D
Taverna
Department of Medical Sciences, University of Turin, Turin, Italy.
Giovanni
G
Camussi
Department of Medical Sciences, University of Turin, Turin, Italy.
Maria Felice
MF
Brizzi
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D024141:Collagen Type IV / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D012323:RNA Processing, Post-Transcriptional; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
D024141:Collagen Type IV; D035683:MicroRNAs; D050799:STAT5 Transcription Factor; D003094:Collagen; D005947:Glucose