Int J Stem Cells.  2021 Aug;14(3):310-319. 10.15283/ijsc20184.

PSC-MSC-Derived Exosomes Protect against Kidney Fibrosis In Vivo and In Vitro through the SIRT6/β-Catenin Signaling Pathway

• Liu L
• Wu Y
• Wang P
• Shi M
• Wang J
• Ma H
• Sun D

• KMID: 2519373
• DOI: http://doi.org/10.15283/ijsc20184

Abstract

Background and Objectives
Chronic kidney disease (CKD) has a major impact on the quality of life of patients, and renal fibrosis is a critical pathological change in the disease. It is very important to control the process of renal fibrosis to improve the quality of life of patients with CKD. The pathological mechanism of renal fibrosis is very complicated, and the current treatment strategy also has many flaws.
Methods and Results
To explore a better treatment, we collected exosomes from pluripotent stem cell (PSC)-derived mesenchymal stem cells (MSC) and verified their therapeutic effect on renal fibrosis through In Vivo and In Vitro experiments. In this study, we found that PSC-MSC-derived comes could prevent the epithelial differentiation of NRK-52E cells, and with increasing exosome concentrations, the effect was improved. Furthermore, PSC-MSC-derived exosomes could reduce the pathological process of renal fibrosis, reduce inflammatory reactions and improve renal function in UUO mice. Moreover, the protective effect of exosomes against renal fibrosis may be achieved by increasing the expression of SIRT6 and decreasing the expression of β-catenin and its downstream products.
Conclusions
These findings suggest the possibility of PSC-MSC-derived exosomes as a new, effective therapeutic tool for kidney fibrosis.

Keyword

Exosomes; Renal fibrosis; UUO; SIRT6

Figure

• 

  Fig. 1 PSC-MSCs-Exosomes inhibit the occurrence of epithelial differentiation in TGF-β1-treated NRK-52E cells. (A) Western blot analysis of Col1-A1, α-SMA and E-cadherin protein expression in NRK-52E cells under different conditions. (B) Real-time PCR analysis of Col1-A1, α-SMA and Fibro gene expression in NRK-52E cells under different conditions. (C) Representative morphology of cells in the different groups. Bar=100 μm. n=3 in each group, ap<0.05 vs. the Con group, bp<0.05 vs. the TGF-β1 group, cp<0.05 vs. the Exo-L group, dp<0.05 vs. the Exo-M group.

• 

  Fig. 2 PSC-MSC-Exosomes inhibited renal fibrosis in UUO mice. (A) Im-munohistochemical staining showed that the expression of fibronectin was inhibited by PSC-MSC-Exo administration in UUO-injured mice. (B) Quantitative results of fibronectin expression. Bar=100 μm. n=3 in each group; ap<0.05 vs. the Con group; bp<0.05 vs. the UUO group.

• 

  Fig. 3 The effect of PSC-MSC-Exo-somes on kidney failure and renal inflammation in UUO mice. (A) TNF-α levels in the different mice. (B) IL-6 levels in the different mice. (C) BUN levels in the different mice. (D) Serum creatinine levels in the different mice. n=6 in each group; ap< 0.05 vs. the Con group; bp<0.05 vs. the UUO group.

• 

  Fig. 4 Mechanism by which exosomes inhibit fibrosis. (A) Western blot analysis of SIRT6 protein expression in the different mice. (B) Western blot analysis of SIRT6 protein expression in NRK-52E cells under different conditions. (C) Repre-sentative immunofluorescence images showing SIRT6 in NRK-52E cells under different conditions. (D) PAI-1, Fsp1 and Axin2 gene expression in NRK-52E cells under different conditions. Bar=50 μm. n=3 in each group; ap<0.05 vs. the Con group; bp<0.05 vs. the TGF-β1 group.

Reference

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