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.
Wang, B., Yao, K., Huuskes, B. M., Shen, H-H., Zhuang, J., Godson, C., Brennan, E. P., Wilkinson-Berka, J. L., Wise, A. F., & Ricardo, S. D. (2016). Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis. Molecular Therapy, 24(7), 1290-1301. https://doi.org/10.1038/mt.2016.90