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Mesenchymal Stem Cells Deliver Exogenous MicroRNA-let7c via Exosomes to Attenuate Renal Fibrosis
Open accessAbstract
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.
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Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. A. (2011) · Nature Biotechnology · doi:10.1038/nbt.1807 · Cited by 4,930
Cited by
Harrell, C. R., Jovicic, N., Djonov, V., Arsenijevic, N., & Volarevic, V. (2019) · Cells · doi:10.3390/cells8121605 · Cited by 795
Liu, W., Li, L., Rong, Y., Qian, D., Chen, J., Zhou, Z., Luo, Y., Jiang, D., Cheng, L., Zhao, S., et al. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.12.020 · Cited by 466
Engineered Extracellular Vesicles for Cancer Therapy
Zhang, X., Zhang, H., Gu, J., Zhang, J., Shi, H., Qian, H., Wang, D., Xu, W., Pan, J., & Santos, H. A. (2021) · Advanced Materials · doi:10.1002/adma.202005709 · Cited by 428
Brennan, M. Á., Layrolle, P., & Mooney, D. J. (2020) · Advanced Functional Materials · doi:10.1002/adfm.201909125 · Cited by 396
Qu, Y., Zhang, Q., Cai, X., Li, F., Ma, Z., Xu, M., & Lu, L. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13170 · Cited by 389
Metadata
- Authors
- 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.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 24
- Issue
- 7
- Pages
- 1290-1301
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2401390149
- Cited by
- 379
- References
- 2
- FWCI
- 13.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
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