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Exosomes derived from mesenchymal stem cells ameliorate renal fibrosis via delivery of miR-186-5p

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Abstract

Evidence has shown that mesenchymal stem cells’ (MSCs) therapy has potential application in treating chronic kidney disease (CKD). In addition, MSCs-derived exosomes can improve the renal function and prevent the progression of CKD. However, the mechanisms by which MSCs-derived exosomes (MSCs-Exo) ameliorate renal fibrosis in CKD remain largely unclear. To mimic an in vitro model of renal fibrosis, rat kidney tubular epithelial cells (NRK52E) were stimulated with transforming growth factor (TGF)-β1. In addition, we established an in vivo model of unilateral ureteric obstruction (UUO)-induced renal fibrosis. Meanwhile, we exploited exosomes derived from MSCs for delivering miR-186-5p agomir into NRK52E cells or kidneys in vitro and in vivo. In this study, we found that level of miR-186-5p was significantly downregulated in TGF-β1-stimulated NRK52E cells and the obstructed kidneys of UUO mice. In addition, miR-186-5p can be transferred from MSCs to NRK52E cells via exosomes. MSCs-delivered miR-186-5p markedly reduced the accumulation of extracellular matrix (ECM) protein, and inhibited epithelial-to-mesenchymal transition (EMT) and apoptosis in TGF-β1-stimulated NRK52E cells. Moreover, exosomal miR-186-5p from MSCs attenuated kidney injury and fibrosis in a UUO mouse model via inhibition of the ECM protein accumulation and EMT process. Meanwhile, dual-luciferase assay showed that miR-186-5p downregulated Smad5 expression via direct binding with the 3′-UTR of Smad5. Collectively then, these findings indicated that exosomal miR-186-5p derived from MSCs could attenuate renal fibrosis in vitro and in vivo by downregulation of Smad5. These findings may help to understand the role of MSCs’ exosomes in alleviating renal fibrosis in CKD.

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Funding

National Natural Scientific Foundation of China (No. 81370868) and Key R & D Program of Jiangsu Province, China (No BE2019712).

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Authors and Affiliations

  1. Department of Pathology and Pathophysiology, Medical School, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China

    Yiqiong Yang, Yu Zhang, Xiuxiu Hu & Li Li

  2. Institute of Andrology, The Affiliated Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China

    Jing Wang

  3. Institute of Nephrology, The Affiliated Zhongda Hospital, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, Jiangsu, 210009, People’s Republic of China

    Pingsheng Chen

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  1. Yiqiong Yang
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Correspondence to Pingsheng Chen.

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All experiments were approved by the Institutional Ethical Committee of the Affiliated Zhongda Hospital, Southeast University, which adheres to the National Institutes of Health Guide for the Care and Use of laboratory animals.

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13577_2021_617_MOESM1_ESM.jpg

Supplementary file1 Supplementary Figure 1 MiR-186-5p level in exosomes derived from transfected MSCs. (A) MiR-186-5p level in MSCs transfected with miR-186-5p antagomir or NC was analyzed by RT-qPCR. **P < 0.01 compared with the NC group. (B) MSCs were transfected with NC or miR-186-5p antagomir for 48 h. RT-qPCR analysis of miR-186-5p levels in exosomes isolated from the CM of transfected MSCs. **P < 0.01 compared with the MSCs/NC group. (C) The level of miR-186-5p in NRK52E cells co-cultured with MSCs transfected with NC or miR-186-5p antagomir. **P < 0.01 compared with the NRK52E + MSCs/NC group. MSCs/NC, MSCs transfected with NC; MSCs/anti-miR-186-5p, MSCs transfected with miR-186-5p antagomir; NC, negative control (JPG 2763 kb)

13577_2021_617_MOESM2_ESM.jpg

Supplementary file2 Supplementary Figure 2 The uptake of exosomes. (A, B) NRK52E cells were co-cultured with exosomes derived from MSCs/miR-186-5p or from MSCs/NC for 48 h. The PKH26 fluorescence signal in cells was observed by confocal microscopy. MSCs/NC-Exo, exosomes derived from MSCs transfected with NC; MSCs/miR-186-5p-Exo, exosomes derived from MSCs transfected with miR-186-5p agomir (JPG 4563 kb)

13577_2021_617_MOESM3_ESM.jpg

Supplementary file3 Supplementary Figure 3 MSCs-secreted anti-miR-186-5p promoted the EMT and apoptosis in TGF-β1-treated NRK52E cells. NRK52E cells were treated with exosomes isolated from the CM of MSCs transfected with NC or miR-186-5p antagomir for 72 h in the presence of TGF-β1. (A) Expressions of collagen III, fibronectin and α-SMA in NRK52E cells were detected with western blotting. (B) Apoptotic cells were detected with Annexin V and PI double staining. (C) Expressions of Bax and active caspase 3 in NRK52E cells were detected with western blotting. *P < 0.05, **P < 0.01. MSCs/NC-Exo, exosomes derived from MSCs transfected with NC; MSCs/anti-miR-186-5p-Exo, exosomes derived from MSCs transfected with miR-186-5p antagomir (JPG 4586 kb)

13577_2021_617_MOESM4_ESM.jpg

Supplementary file4 Supplementary Figure 4 MiR-186-5p agomir alleviated renal fibrosis in UUO mice. (A, B) The levels of BUN and CR in serum of mice were detected by ELISA. (C) H&E staining assay was used to determine kidney injury in UUO kidneys. (D) Masson’s trichrome staining assay was used to determine collagen deposition and renal fibrosis in UUO kidneys. **P < 0.01 compared with sham group; #P < 0.05, ##P < 0.01 compared with NC + UUO group (JPG 9340 kb)

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Yang, Y., Wang, J., Zhang, Y. et al. Exosomes derived from mesenchymal stem cells ameliorate renal fibrosis via delivery of miR-186-5p. Human Cell 35, 83–97 (2022). https://doi.org/10.1007/s13577-021-00617-w

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