https://ror.org/02z43xh36 Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA.
Department of Genetics, Rutgers University, Piscataway, NJ, USA.
Life Sci Alliance. 2024 Oct 4;7(12). doi: 10.26508/lsa.202402935. Print 2024 Dec.
Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel disease. But the epithelial-specific contribution to mucosal healing in vivo is poorly understood. We evaluated mucosal healing in an acute dextran sulfate sodium mouse model that shows an alleviated colitis response after epithelial-specific loss of Smad4. We find that enhanced epithelial wound healing alleviates the fibrotic response. Dextran sulfate sodium caused increased mesenchymal collagen deposition-indicative of fibrosis-within a week in the WT but not in the Smad4 KO colon. The fibrotic response correlated with decreased epithelial proliferation in the WT, whereas uninterrupted proliferation and an expanded zone of proliferation were observed in the Smad4 KO colon epithelium. Furthermore, the Smad4 KO colon showed epithelial extracellular matrix alterations that promote epithelial regeneration. Our data suggest that epithelium is a key determinant of the mucosal healing response in vivo, implicating mucosal healing as a strategy against fibrosis in inflammatory bowel disease patients.
黏膜愈合与炎症性肠病患者的临床转归相关。但上皮细胞对体内黏膜愈合的特异性作用仍知之甚少。我们在急性葡聚糖硫酸钠（DSS）诱导的小鼠模型中评估黏膜愈合，该模型中上皮细胞特异性 Smad4 缺失后结肠炎反应减轻。我们发现增强的上皮细胞愈合可减轻纤维化反应。WT 结肠中 DSS 诱导的间质胶原沉积增加（提示纤维化）在一周内即可观察到，而 Smad4 KO 结肠中则观察不到。WT 中纤维化反应与上皮细胞增殖减少相关，而 Smad4 KO 结肠上皮细胞中观察到持续增殖和增殖区扩大。此外，Smad4 KO 结肠中上皮细胞外基质改变，促进上皮细胞再生。我们的数据表明，上皮细胞是体内黏膜愈合反应的关键决定因素，提示黏膜愈合是炎症性肠病患者对抗纤维化的策略。
