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RESEARCH PRODUCT

Stem Cell-Derived, microRNA-Carrying Extracellular Vesicles: A Novel Approach to Interfering with Mesangial Cell Collagen Production in a Hyperglycaemic Setting.

Gabriele TogliattoAlberto RossettiGiusy LombardoMaria Chiara DeregibusMaria Felice BrizziSara GalloGiovanni CamussiMaddalena GiliDaniela TavernaPatrizia DentelliArturo Rosso

subject

0301 basic medicineMolecular biologyCellGene Expressionlcsh:MedicineBiochemistry0302 clinical medicineAnimal CellsChronic Kidney DiseaseMedicine and Health SciencesSTAT5 Transcription FactorRNA Processing Post-Transcriptionallcsh:ScienceSTAT5Energy-Producing OrganellesCells CulturedMultidisciplinarybiologyMesangial cellStem CellsVector ConstructionCell biologyMitochondriaEnzymesmedicine.anatomical_structureBiochemistryNephrology030220 oncology & carcinogenesisMesangial CellsCollagenStem cellCellular TypesCellular Structures and OrganellesOxidoreductasesLuciferaseResearch ArticleCollagen Type IVBioenergeticsDNA constructionModels Biological03 medical and health sciencesExtracellular VesiclesmicroRNAmedicineGene Expression and Vector TechniquesGeneticsHumansVesiclesCell ProliferationMolecular Biology Assays and Analysis TechniquesCell growthMesenchymal stem celllcsh:RBiology and Life SciencesProteinsMesenchymal Stem CellsTransforming growth factor betaCell BiologyResearch and analysis methodsMicroRNAs030104 developmental biologyMolecular biology techniquesGlucoseHyperglycemiabiology.proteinEnzymologylcsh:QCollagens

description

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.

10.1371/journal.pone.0162417http://europepmc.org/articles/PMC5017750?pdf=render