Human umbilical cord mesenchymal stem cells alleviate colon epithelial apoptosis in ulcerative colitis by activating inositol-requiring enzyme 1/X-box binding protein 1 signaling.

Abstract

Background: Ulcerative colitis (UC), a chronic inflammatory gastrointestinal disease, is characterized by disrupted intestinal barrier integrity and unresolved endoplasmic reticulum (ER) stress, which drives epithelial apoptosis and disease progression. While mesenchymal stem cells (MSCs), particularly human umbilical cord-derived MSCs (hUC-MSCs), have shown therapeutic potential in UC, their mechanisms in modulating ER stress remain unclear. This study aimed to investigate the role of hUC-MSCs in alleviating ER stress-induced epithelial damage and elucidate the underlying molecular pathways in a murine colitis model and in vitro systems.

Results: Intraperitoneal administration of hUC-MSCs significantly attenuated dextran sulfate sodium (DSS)-induced colitis in mice. Histological analysis revealed restored crypt architecture and reduced epithelial apoptosis. Transcriptomic profiling demonstrated that hUC-MSCs reduced differentially expressed genes in inflammatory bowel disease-related and ER stress response pathways in colon tissues. Mechanistically, hUC-MSCs activated the IRE1/XBP1 axis, increasing Xbp1 splicing and suppressing pro-apoptotic Bcl2l11 expression. In vitro, hUC-MSC-conditioned medium protected colon epithelial cells from TNF-α-induced apoptosis via IRE1/XBP1 activation, an effect abolished by the IRE1 inhibitor 4μ8C.

Conclusions: Our findings demonstrate that hUC-MSCs alleviate UC by mitigating ER stress through IRE1-mediated Xbp1 splicing, thereby reducing epithelial apoptosis and promoting mucosal repair. This study provides a mechanistic foundation for MSC-based therapies targeting ER stress in inflammatory bowel diseases.