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 (), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased () 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.

中文翻译：

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胎盘间充质基质细胞 (PMSC) 和 PMSC 衍生的细胞外囊泡 (PMSC-EV) 通过调节 CD4+ T 细胞极化减轻单侧输尿管梗阻 (UUO) 大鼠的肾纤维化。

目的。最近的证据表明，CD4 ⁺ T 辅助 (Th) 细胞与肾脏炎症和纤维化有关。^{然而，是否可以通过干预CD4 +} T细胞的极化来缓解肾纤维化仍是未知数。我们的研究调查了静脉注射胎盘间充质基质细胞 (PMSCs) 或用源自 PMSCs (PMSC-EVs) 的细胞外 EVs (EVs) 治疗对单侧输尿管梗阻 (UUO) 大鼠CD4 ^{+ T 细胞极化的影响。}我们进一步验证了 PMSCs 如何在体外影响炎症因子分泌以及调节性 T (Treg) 和 Th17 CD4 ⁺ T 细胞的水平。材料和方法. 我们通过病理切片染色评估肾间质炎症和纤维化，通过流式细胞术（FCM）和免疫组织化学检测CD4 ⁺ T细胞（Th17和Treg表型）的极化，并通过酶联免疫吸附检测CD4 ⁺ T细胞分泌的细胞因子测定法（ELISA）。结果。与对照大鼠相比，PMSC 治疗大鼠的肾组织表现出较低的肾脏 Masson 评分和更多的 Foxp3 ⁺细胞浸润，IL17A ⁺ CD4 ⁺ T 细胞/CD4 ⁺ T 细胞比率显着降低，抗炎作用显着升高细胞因子 (IL-10) 水平。当 CD4 ⁺T 细胞与 PMSCs 共培养，在 UUO 模型中与 PMSCs 共培养 7 天后CD4 ⁺ IL17A ^{+细胞百分比降低。}TGF- β和IL-10的分泌明显增加（)，而 IFN- γ、IL-17 和 IL-6 的分泌明显减少 ()在 PMSC 共培养组中。此外，PMSC-EVs 治疗后第 7 天，UUO 模型动物肾脏中的肾小管间质纤维化得到缓解，Foxp3 ⁺ /IL-17 ^{+细胞浸润增加。}结论。PMSCs通过影响CD4 ⁺ T细胞和巨噬细胞的极化，抑制炎症因子IFN- γ和IL-17，上调抗炎因子TGF- β和IL-10，最终导致肾脏保护。这些功能可能是由 PMSC-EV 的旁分泌活动介导的。