Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4+ T Cell Polarization

Zhu Zhu; Chaonan Han; Shuli Xian; Feng Zhuang; Feng Ding; Wei Zhang; Yingli Liu

doi:10.1155/2020/2685820

Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4⁺ T Cell Polarization

Stem Cells Int. 2020 Jul 22:2020:2685820. doi: 10.1155/2020/2685820. eCollection 2020.

Authors

Zhu Zhu¹, Chaonan Han¹, Shuli Xian¹, Feng Zhuang¹, Feng Ding¹, Wei Zhang¹, Yingli Liu¹

Affiliation

¹ Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Abstract

Purpose: Recent evidence has shown that CD4⁺ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4⁺ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4⁺ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4⁺ T cells in vitro.

Materials and methods: We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4⁺ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4⁺ T cells by enzyme-linked immunosorbent assay (ELISA).

Results: Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3⁺ cell infiltration, with a significantly decreased IL17A⁺CD4⁺ T cell/CD4⁺ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4⁺ T cells were cocultured with PMSCs, CD4⁺IL17A⁺ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P < 0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P < 0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3⁺/IL-17⁺ cell infiltration was increased in the kidneys of UUO model animals on day 7.

Conclusions: PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4⁺ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.