DataSheet_1_Intraperitoneally Delivered Mesenchymal Stem Cells Alleviate Experimental Colitis Through THBS1-Mediated Induction of IL-10-Competent Regulatory B Cells.pdf

Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD), and intraperitoneal delivery of MSCs have become a more effective route for IBD treatment. However, the underlying mechanisms are still poorly understood. Here, we found that intraperitoneally delivered MSCs significantly alleviated experimental colitis. Depletion of peritoneal B cells, but not macrophages, clearly impaired the therapeutic effects of MSCs. Intraperitoneally delivered MSCs improved IBD likely by boosting the IL-10-producing B cells in the peritoneal cavity, and a single intraperitoneal injection of MSCs could significantly prevent disease severity in a recurrent mouse colitis model, with lower proinflammation cytokines and high level of IL-10. The gene expression profile revealed that thrombospondin-1 (THBS1) was dramatically upregulated in MSCs after coculture with peritoneal lavage fluid from colitis mice. Knockout of THBS1 expression in MSCs abolished their therapeutic effects in colitis and the induction of IL-10-producing B cells. Mechanistically, THBS1 modulates the activation of transforming growth factor-β (TGF-β), which combines with TGF-β receptors on B cells and contributes to IL-10 production. Blocking the interaction between THBS1 and latent TGF-β or inhibiting TGF-β receptors (TGF-βR) significantly reversed the THBS1-mediated induction of IL-10-producing B cells and the therapeutic effects on colitis. Collectively, our study revealed that intraperitoneally delivered MSCs secreted THBS1 to boost IL-10+Bregs and control the progression and recurrence of colitis, providing new insight for the prevention and treatment of IBD.

间充质干细胞（Mesenchymal stem cells, MSCs）在炎症性肠病（inflammatory bowel disease, IBD）的治疗中展现出极具潜力的治疗价值，而腹腔递送MSCs已成为IBD治疗的更高效途径。然而，其发挥治疗作用的潜在分子机制仍未被充分阐明。本研究发现，腹腔递送的MSCs可显著缓解实验性结肠炎。清除腹膜B细胞（而非巨噬细胞）会明显削弱MSCs的治疗效果。腹腔递送的MSCs或通过扩增腹膜腔内产生IL-10的B细胞来改善IBD症状；单次腹腔注射MSCs即可显著抑制复发性小鼠结肠炎模型的疾病严重程度，同时降低促炎细胞因子水平并维持较高的IL-10表达量。基因表达谱分析显示，在与结肠炎小鼠腹腔灌洗液共培养后，MSCs内的血小板反应蛋白-1（thrombospondin-1, THBS1）表达显著上调。敲除MSCs中的THBS1基因表达会完全消除其对结肠炎的治疗效果，以及对产生IL-10的B细胞的诱导能力。从机制层面来看，THBS1可调控转化生长因子-β（transforming growth factor-β, TGF-β）的活化，后者可结合B细胞表面的TGF-β受体，进而促进IL-10的产生。阻断THBS1与潜伏态TGF-β的相互作用，或抑制TGF-β受体（TGF-βR），均可显著逆转THBS1介导的产生IL-10的B细胞诱导效应，以及其对结肠炎的治疗作用。综上，本研究揭示腹腔递送的MSCs可通过分泌THBS1，增强IL-10+调节性B细胞（Bregs）的功能，从而调控结肠炎的进展与复发，为IBD的预防与治疗提供了全新的研究思路。