Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis

Bo Wang, Kevin Yao, Brooke M Huuskes, Hsin-Hui Shen, Junli Zhuang, Catherine Godson, Eoin P Brennan, Jennifer L Wilkinson-Berka, Andrea F Wise, Sharon D Ricardo

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117 Citations (Scopus)

Abstract

The advancement of microRNA (miRNA) therapies has been hampered by difficulties in delivering miRNA to the injured kidney in a robust and sustainable manner.Using bioluminescence imaging in mice with unilateral ureteral obstruction (UUO), we report that mesenchymal stem cells (MSCs), engineered to over express miRNA-let7c (miR-let7c-MSCs), selectively homed to damaged kidneys and upregulated miR-let7c gene expression, compared with nontargeting control (NTC)-MSCs. miR-let7c-MSC therapy attenuated kidney injury and significantly downregulated collagen IVα1, metal-loproteinase-9, transforming growth factor (TGF)-β1,and TGF-β type 1 receptor (TGF-βR1) in UUO kidneys,compared with controls. In vitro analysis confirmed that the transfer of miR-let7c from miR-let7c-MSCs occurredvia secreted exosomal uptake, visualized in NRK52Ecells using cyc3-labeled pre-miRNA-transfected MSCswith/without the exosomal inhibitor, GW4869. The upregulated expression of fibrotic genes in NRK52E cells induced by TGF-β1 was repressed following the addition of isolated exosomes or indirect coculture of miR-let7c-MSCs, compared with NTC-MSCs. Furthermore, the cotransfection of NRK52E cells using the 3′UTR of TGF-βR1 confirmed that miR-let7c attenuates TGF-β1-drivenTGF-βR1 gene expression. Taken together, the effective antifibrotic function of engineered MSCs is able to selectively transfer miR-let7c to damaged kidney cells and willpave the way for the use of MSCs for therapeutic delivery of miRNA targeted at kidney disease.
Original languageEnglish
Pages (from-to)1290-1301
Number of pages12
JournalMolecular Therapy
Volume24
Issue number7
DOIs
Publication statusPublished - 2016

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