Department of Gastrointestinal Surgery, Department of General Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of General Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Int Immunopharmacol. 2024 Sep 30;139:112693. doi: 10.1016/j.intimp.2024.112693. Epub 2024 Jul 17.
The therapeutic potential of adipose-derived mesenchymal stromal cells (AMSCs) in the treatment of intestinal fibrosis occured in patients with Crohn's disease (CD) remains unclear. Tumor necrosis factor-stimulated gene 6 (TSG6) protein plays a critical role in inflammation regulation and tissue repair. This study aimed to determine if AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein and explore the underlying mechanisms.
Two murine models for intestinal fibrosis were established using 2,4,6-trinitrobenzene sulfonic acid in BALB/c mice and dextran sulfate sodium in C57BL/6 mice. Primary human fibroblasts and CCD-18co cells were incubated with transforming growth factor (TGF)-β1 to build two fibrosis cell models in vitro.
Intraperitoneally administered AMSCs attenuated intestinal fibrosis in the two murine models, as evidenced by significant alleviation of colon shortening, collagen protein deposits, and submucosal thickening, and also decrease in the endoscopic and fibrosis scores (P < 0.001). Although intraperitoneally injected AMSCs did not migrate to the colon lesions, high levels of TSG6 expression and secretion were noticed both in vivo and in vitro. Similar to the role of AMSCs, injection of recombinant human TSG6 attenuated intestinal fibrosis in the mouse models, which was not observed with the administration of AMSCs with TSG6 knockdown or TSG6 neutralizing antibody. Mechanistically, TSG6 alleviates TGF-β1-stimulated upregulation of α-smooth muscle actin (αSMA) and collagen I by inhibiting Smad2 phosphorylation. Furthermore, the expression of TSG6 is lower in intestinal fibrosis tissue of patients with Crohn's disease and can reduce pro-fibrotic protein (αSMA) secretion from primary ileal fibrotic tissue.
AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein, which inhibits Smad2 phosphorylation. TSG6, a novel anti-fibrotic factor, could potentially improve intestinal fibrosis treatments.
脂肪间充质基质细胞（AMSCs）在治疗克罗恩病（CD）患者的肠道纤维化中的治疗潜力尚不清楚。肿瘤坏死因子刺激基因 6（TSG6）蛋白在炎症调节和组织修复中起着关键作用。本研究旨在确定 AMSCs 是否通过分泌旁分泌 TSG6 蛋白来减轻肠道纤维化，并探讨其潜在机制。
使用 2,4,6-三硝基苯磺酸在 BALB/c 小鼠和葡聚糖硫酸钠在 C57BL/6 小鼠中建立了两种肠道纤维化模型。体外将原代人成纤维细胞和 CCD-18co 细胞与转化生长因子（TGF）-β1 孵育，建立两种纤维化细胞模型。
腹腔内给予 AMSCs 可减轻两种小鼠模型中的肠道纤维化，表现为结肠缩短、胶原蛋白沉积和黏膜下增厚明显缓解，内镜和纤维化评分降低（P<0.001）。虽然腹腔内注射的 AMSCs 未迁移到结肠病变部位，但在体内和体外均观察到高水平的 TSG6 表达和分泌。与 AMSCs 的作用相似，注射重组人 TSG6 可减轻小鼠模型中的肠道纤维化，而用 TSG6 敲低的 AMSCs 或 TSG6 中和抗体给药则观察不到这种作用。机制上，TSG6 通过抑制 Smad2 磷酸化减轻 TGF-β1 刺激的α-平滑肌肌动蛋白（αSMA）和胶原 I 的上调。此外，克罗恩病患者肠道纤维化组织中 TSG6 的表达较低，可减少原代回肠纤维化组织中促纤维化蛋白（αSMA）的分泌。
AMSCs 通过分泌旁分泌 TSG6 蛋白减轻肠道纤维化，该蛋白抑制 Smad2 磷酸化。TSG6 作为一种新型抗纤维化因子，可能改善肠道纤维化的治疗效果。
