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

Abstract

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.

Protective Role of Stem Cell Derived Extracellular Vesicles in an In Vitro Model of Hyperglycemia-Induced Endothelial Injury

“…This data suggests that EVs may play an anti-oxidant role. Consistent with our previous data [45] the present data suggest that EVs may play an antioxidant role.…”

Extracellular Vesicles in Renal Pathophysiology

“…This occurs via the horizontal transfer of functional miR-222, resulting in STAT5 down-regulation, and a decrease in miR-21 content, TGFβ expression and matrix protein synthesis (Gallo et al, 2016). …”

PDGF-BB Carried by Endothelial Cell–Derived Extracellular Vesicles Reduces Vascular Smooth Muscle Cell Apoptosis in Diabetes

“…Total RNA was isolated from the VSMCs of atherosclerotic plaque specimens and from human VSMCs, that had been treated as indicated or left untreated, using the TRIzol reagent (Invitrogen) as previously described (26). RNA from cells and EVs was then reverse transcribed using a TaqMan MicroRNA Reverse Transcription Kit, specific for miR-24-3p, miR-221, miR-222, and miR-296-5p, or a SYBR Green miRNA reverse transcription kit specific for miR-21-5p, miR-29a, and miR-145, as indicated.…”