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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Wang, Bo ; Yao, Kevin ; Huuskes, Brooke M ; Shen, Hsin-Hui ; Zhuang, Junli ; Godson, Catherine ; Brennan, Eoin P ; Wilkinson-Berka, Jennifer L ; Wise, Andrea F ; Ricardo, Sharon D. / Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis. In: Molecular Therapy. 2016 ; Vol. 24, No. 7. pp. 1290-1301.
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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 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.",
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Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis. / Wang, Bo; Yao, Kevin; Huuskes, Brooke M; Shen, Hsin-Hui; Zhuang, Junli; Godson, Catherine; Brennan, Eoin P; Wilkinson-Berka, Jennifer L; Wise, Andrea F; Ricardo, Sharon D.

In: Molecular Therapy, Vol. 24, No. 7, 2016, p. 1290-1301.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis

AU - Wang, Bo

AU - Yao, Kevin

AU - Huuskes, Brooke M

AU - Shen, Hsin-Hui

AU - Zhuang, Junli

AU - Godson, Catherine

AU - Brennan, Eoin P

AU - Wilkinson-Berka, Jennifer L

AU - Wise, Andrea F

AU - Ricardo, Sharon D

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/27203438

U2 - 10.1038/mt.2016.90

DO - 10.1038/mt.2016.90

M3 - Article

VL - 24

SP - 1290

EP - 1301

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 7

ER -