我国克罗恩病(CD)发病率逐年升高，疗效不理想，致残率高。间充质干细胞(MSC)为CD治疗带来新希望，iPSC来源的MSC(iPSC-MSC)能克服MSC存在的复制性衰老、干性丢失等缺陷。我们前期研究发现iPSC-MSC可修复结肠炎小鼠黏膜损伤，同时体内Breg上调、T细胞亚群失衡纠正，miRNA网络改变、黏膜屏障修复及Notch通路激活。肠黏膜愈合是CD治疗的新目标，而黏膜免疫平衡、屏障修复及肠上皮干细胞激活是黏膜愈合的三大关键环节。基于此，我们提出假说：iPSC-MSC通过Breg细胞改善肠道炎症微环境，进而通过miRNA-紧密连接相关基因重建肠黏膜屏障，并通过PRRs-Notch-STAT5轴活化肠上皮干细胞，从而促进肠黏膜愈合。本研究以结肠炎小鼠及微小肠模型为研究载体，进一步证实iPSC-MSC促进CD黏膜愈合的效果并系统研究其机制，为临床治疗CD的转化应用提供依据。

Crohn’s disease (CD) often presents in early age and commonly manifests with chronic relapsing debilitating symptoms and severe complications. With continuously increasing incidence in China, CD becomes one of the most common diseases in the gastroenterology field. However, no cure for CD until now and the current treatments are difficult to achieve and maintain remission, which results in up to 80% CD patients need for abdominal surgeries for severe complications. Therefore, it remains a great need for new therapies that are both effective and safe. Recent studies have shown that the transplantation of Mesenchymal Stem Cell (MSC) is an alternative therapeutic option to CD, but the characteristics of the MSCs including replicative senescence causing losing stem cell capacity need to be solved before application in the clinical therapy. Induced Pluripotent Stem Cell (iPSC)-derived MSCs is expected to overcome these disadvantages. Our preliminary research has shown that the iPSC-derived MSCs has stronger proliferative capacity and are more effective in colitis repair. We found that the improvement of intestinal mucosal healing is accompanied by the rebuilt of Treg/Th1/Th17 balance, the increase number of regulatory B cells (Bregs) and the change of miRNA network which leads to the improvement of epithelial barrier. Furthermore, we previously identified that MSC-activated PRRs-Notch-STAT5 axis may be involved in the activation of intestinal epithelial stem cell (IESC). Mucosal healing in CD is a tightly controlled process associated with suppression of inflammation and improvement of intestinal barrier function. It is also dependent on the balance of migration, proliferation and functional differentiation of IECs adjacent to the injured area. Based on our previous data, we proposed to test the hypothesis that iPSC-derived MSCs promotes mucosal healing in CD through the mechanism by which Bregs mediates the rebuilt of Treg/Th1/Th17 balance, miRNA network regulates epithelial barrier and inflammatory microenvironment activates IESC by PRRs-Notch-STAT5 axis. We will test our hypothesis by applying iPSC-derived MSC in multiple research models including clinical CD patients’ intestinal samples, trinitrobenzesulfonic acid (TNBS)-induced colitis mice models and the murine-derived intestinal organoids and then analyzing the regulation of iPSC-derived MSC in immunomodulation, epithelial barrier and activation of IESC. We aim to delineate the mechanism of iPSC-derived MSC in promoting mucosal healing. As such, the anticipated results will provide novel therapeutic approaches for CD, explore new target of therapeutic intervention and improve the clinical outcomes of CD patients.