Journal
MOLECULAR THERAPY
Volume 24, Issue 7, Pages 1290-1301Publisher
CELL PRESS
DOI: 10.1038/mt.2016.90
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Funding
- Monash University
- Kidney Health Australia
- Science Foundation Ireland Awards [06/IN/.1/B114, 08/US/B1517]
- Science Foundation Ireland (SFI) [06/IN.1/B114, 08/US/B1517] Funding Source: Science Foundation Ireland (SFI)
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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 overexpress 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 IV alpha 1, metalloproteinase-9, transforming growth factor (TGF)-beta 1, and TGF-beta type 1 receptor (TGF-beta R1) in UUO kidneys, compared with controls. In vitro analysis confirmed that the transfer of miR-let7c from miR-let7c-MSCs occurred via secreted exosomal uptake, visualized in NRK52E cells using cyc3-labeled pre-miRNA-transfected MSCs with/without the exosomal inhibitor, GW4869. The upregulated expression of fibrotic genes in NRK52E cells induced by TGF-beta 1 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-beta R1 confirmed that miR-let7c attenuates TGF-beta 1-driven TGF-beta R1 gene expression. Taken together, the effective antifibrotic function of engineered MSCs is able to selectively transfer miR-let7c to damaged kidney cells and will pave the way for the use of MSCs for therapeutic delivery of miRNA targeted at kidney disease.
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