title: Mesenchymal Stem Cells Deliver Exogenous MicroRNA-let7c via Exosomes to Attenuate Renal Fibrosis.
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 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 IVα1, metalloproteinase-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 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-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-driven TGF-βR1 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.
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yao
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Huuskes
authors.affiliation: Department of Microbiology, Monash University, Victoria, Australia.
authors.forename: Hsin-Hui
authors.initials: HH
authors.lastname: Shen
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Junli
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Diabetes Complications Research Centre, Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.affiliation: Diabetes Complications Research Centre, Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Brennan
authors.affiliation: Department of Immunology, Monash University, Victoria, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Wise
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D060846:Cell Engineering; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051381:Rats; D014161:Transduction, Genetic
chemical_list: D000199:Actins; D035683:MicroRNAs; D003094:Collagen; D066246:ErbB Receptors