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.

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 IL17ACD4 T cell/CD4 T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4 T cells were cocultured with PMSCs, CD4IL17A cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF- and IL-10 was significantly increased ( < 0.05), while the secretion of IFN-, IL-17, and IL-6 was significantly decreased ( < 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- and IL-17, and upregulating the expression of the anti-inflammatory factors TGF- and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.