Sepsis remains a leading cause of death in critically ill patients. It is well known that mesenchymal stem cells (MSCs) are a promising therapy partly due to their paracrine-mediated immunoregulatory function. Previous study demonstrated that transforming growth factor-beta1 (TGF-β1) is an important cytokine secreted by MSCs and that it participates in MSC-mediated macrophage phenotype switch from pro-inflammatory to pro-resolution. In addition, the transformation of macrophage phenotype may be a potential treatment for sepsis. However, the therapeutic effect of overexpressing TGF-β1 in MSCs (MSC-TGF-β1) on sepsis is not well understood. Therefore, this study aimed to evaluate the effects of TGF-β1 overexpressing MSCs on organ injury in cecal ligation and puncture (CLP)-induced septic mice and to detect the changes in macrophage phenotype during this process. Mouse MSCs stably transfected with TGF-β1 were constructed and injected into CLP-induced septic mice via tail vein. After 24 h, the mice were sacrificed; then, the histopathology of the organ was evaluated by hematoxylin-eosin (H&E) staining. Inflammatory cytokines were detected by ELISA. Macrophage infiltration and phenotype transformation in the tissues were determined by immunohistochemistry and flow cytometry. In addition, we performed adoptive transfer of mouse peritoneal macrophage pretreated with TGF-β1 overexpressing MSCs in septic mice. We found that infusion of TGF-β1 overexpressing MSCs attenuated the histopathological impairment of the organ, decreased the pro-inflammatory cytokine levels and inhibited macrophage infiltration in tissues. TGF-β1 overexpressing MSCs induced macrophage phenotypes changed from pro-inflammatory to pro-resolution in inflammatory environment. The adoptive transfer of mouse peritoneal macrophages pretreated with TGF-β1 overexpressing MSCs also relieved organ damage in CLP-induced septic mice. Under septic conditions, TGF-β1 overexpressing MSCs can enhance the therapeutic effects of MSCs on organ injury and inflammation as a result of reduced macrophage infiltration and induced macrophages transformation, the adoptive transfer of macrophages treated with TGF-β1 overexpressing MSCs also relieved organ damage. This will provide new hope for the treatment of sepsis.

中文翻译：

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在间充质干细胞中过表达 TGF-β1 通过减少巨噬细胞驱动的炎症来减轻 CLP 诱导的脓毒症小鼠的器官功能障碍。

脓毒症仍然是危重患者死亡的主要原因。众所周知，间充质干细胞 (MSCs) 是一种很有前途的治疗方法，部分原因是它们具有旁分泌介导的免疫调节功能。先前的研究表明，转化生长因子-β1 (TGF-β1) 是 MSC 分泌的一种重要细胞因子，它参与了 MSC 介导的巨噬细胞表型从促炎到促消退的转变。此外，巨噬细胞表型的转化可能是脓毒症的潜在治疗方法。然而，在 MSCs (MSC-TGF-β1) 中过表达 TGF-β1 对脓毒症的治疗效果尚不清楚。所以，本研究旨在评估过表达 TGF-β1 的 MSCs 对盲肠结扎和穿刺 (CLP) 诱导的脓毒症小鼠器官损伤的影响，并检测此过程中巨噬细胞表型的变化。构建稳定转染TGF-β1的小鼠MSCs并通过尾静脉注射到CLP诱导的脓毒症小鼠体内。24小时后处死小鼠；然后，通过苏木精 - 伊红（H＆E）染色评估器官的组织病理学。通过ELISA检测炎症细胞因子。通过免疫组织化学和流式细胞术确定组织中的巨噬细胞浸润和表型转化。此外，我们在脓毒症小鼠中对用过表达 TGF-β1 的 MSCs 预处理的小鼠腹腔巨噬细胞进行过继转移。我们发现输注过表达 TGF-β1 的 MSC 可减轻器官的组织病理学损伤，降低促炎细胞因子水平并抑制组织中的巨噬细胞浸润。过表达 TGF-β1 的 MSCs 诱导巨噬细胞表型在炎症环境中从促炎转变为促消退。用过表达 TGF-β1 的 MSC 预处理的小鼠腹腔巨噬细胞的过继转移也减轻了 CLP 诱导的脓毒症小鼠的器官损伤。在脓毒症条件下，过表达TGF-β1的MSCs可以通过减少巨噬细胞浸润和诱导巨噬细胞转化来增强MSCs对器官损伤和炎症的治疗作用，过表达TGF-β1的MSCs处理的巨噬细胞的过继转移也减轻了器官损伤。