Rationale: Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD) due to their immunomodulatory and trophic functions. However, their efficacy is influenced by tissue origin, donator condition, isolation, and expansion methods. Here, we generated phenotypically uniform MSCs from human embryonic stem cells (T-MSCs) and explored the molecular mechanisms involved in promoting mucosal integrity and regeneration in colitis mice./nMethods: T-MSCs were injected intravenously into mice with dextran sulfate sodium (DSS)-induced colitis, and the in vivo distribution and therapeutic efficacy were evaluated. We performed serum cytokine antibody microarrays to screen potentially effective proteins and examined the therapeutic effect of insulin-like growth factor-1 (IGF-1). Colon epithelial regeneration potential was evaluated, and RNA sequencing was employed to determine the underlying molecular mechanisms. Finally, in vitro IGF-1 stimulation was performed to assess its effect on cell functions and organoid growth./nResults: Intravenous administration of T-MSCs alleviated colitis in both acute and chronic DSS mouse models. Labeled T-MSCs were mainly distributed in the lungs, liver, and spleen after systemic infusion. The antibody array analysis of serum cytokines indicated that the IGF-1 level was increased in the treatment group, and serum ELISA further confirmed its elevation in the regeneration stage. Intraperitoneal injection of IGF-1 receptor inhibitors abrogated the anti-inflammatory activity of T-MSCs. The colonic epithelium of the treatment group showed greater regenerative potency than the controls and the IGF1R-PI3K-AKT pathway was up-regulated. RNA sequencing showed that T-MSC treatment contributed to colonic cell integrity and promoted xenobiotic metabolism. In vitro IGF-1 stimulation promoted the growth and proliferation of colon cells and organoids./nConclusions: Intravenous infusion of T-MSCs alleviated colitis in mice by elevating the circulating IGF-1 level. Increased IGF-1 maintained the integrity of epithelial cells and contributed to their repair and regeneration. Our study has identified T- MSCs as a potential cell resource for IBD treatment.

中文翻译：

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胚胎干细胞来源的间充质干细胞通过升高结肠炎小鼠中的循环IGF-1来促进结肠上皮完整性和再生

基本原理：间充质干细胞（MSC）由于具有免疫调节和营养功能，因此在治疗炎症性肠病（IBD）方面显示出有希望的治疗潜力。但是，它们的功效受组织来源，捐赠者状况，分离和扩增方法的影响。在这里，我们从人胚胎干细胞（T-MSC）生成表型统一的MSC，并探讨了促进结肠炎小鼠粘膜完整性和再生的分子机制。/n方法：将T-MSC静脉内注射硫酸葡聚糖硫酸钠（ DSS）诱发的结肠炎，以及体内评估其分布和疗效。我们进行了血清细胞因子抗体微阵列筛选可能有效的蛋白质，并检查了胰岛素样生长因子-1（IGF-1）的治疗效果。评估结肠上皮再生的潜力，并采用RNA测序确定潜在的分子机制。最后，在体外IGF-1刺激下进行，以评估其对细胞的功能和类器官growth./n效果结果：在急性和慢性DSS小鼠模型中，静脉内施用T-MSC均减轻了结肠炎。全身性输注后，标记的T-MSCs主要分布在肺，肝和脾中。血清细胞因子的抗体阵列分析表明，治疗组的IGF-1水平升高，血清ELISA进一步证实了其在再生阶段的升高。腹膜内注射IGF-1受体抑制剂消除了T-MSC的抗炎活性。与对照组相比，治疗组的结肠上皮显示出更高的再生能力，并且IGF1R-PI3K-AKT途径被上调。RNA测序表明，T-MSC处理有助于结肠细胞完整性并促进异种生物代谢。体外IGF-1刺激促进结肠细胞和类器官的生长和增殖。/n结论： T-MSC静脉输注可通过提高循环IGF-1水平减轻小鼠结肠炎。增加的IGF-1维持上皮细胞的完整性，并有助于其修复和再生。我们的研究确定了T-MSCs是IBD治疗的潜在细胞资源。