Wang Lu, Wang Shu, Lin Junjie, Li Jiajia, Wang Mingyuan, Yu Jiang, Sun Junjian, Tang Nana, Jiao Chunhua, Ma Jingjing, Zhao Xiaojing, Zhang Hongjie
Department of Gastroenterology, First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
J Transl Med. 2025 Apr 17;23(1):452. doi: 10.1186/s12967-025-06413-6.
Intestinal fibrosis is a serious complication of Crohn's disease (CD), often resulting from chronic inflammation. However, the precise mechanisms through which inflammation induces intestinal fibrosis remain inadequately elucidated.
A comprehensive single-cell atlas of full-thickness CD, provided by Dr. Florian Rieder, was subjected to reanalysis. Our study used a DSS-induced chronic colitis model in both wild-type (WT) and Areg mice. Additionally, a CD45RB CD4 T cell adoptive transfer model involving WT and Areg Treg cells (Tregs) was used. The expressions of AREG in CD with or without intestinal fibrosis, Tregs and human intestinal myofibroblasts (MFs) were determined. The effect of AREG on proliferation/migration/activation in human intestinal MFs was determined.
Several types of cells were differentially expressed between stricture and non-stricture CD. Among T cells, Tregs accounted for a larger proportion and were significantly increased in stenotic tissues of stricture CD. Although DSS-induced colitis was more severe in Areg mice, which developed less severe intestinal fibrosis compared with WT mice. The transfer of Areg Tregs resulted in less severe fibrosis in Rag mice than WT Tregs. Moreover, TGF-β stimulated AREG expression in Tregs and human intestinal MFs via activation of Smad3.
These findings demonstrated that AREG derived from Tregs and human intestinal MFs, induced by TGF-β, amplifies intestinal fibrotic reactions in experimental colitis as well as in human CD patients. Thus, the TGF-β-Smad3-AREG pathway could be a potential therapeutic target for treating fibrosis in CD.
肠道纤维化是克罗恩病（CD）的一种严重并发症，通常由慢性炎症引起。然而，炎症诱导肠道纤维化的确切机制仍未得到充分阐明。
对弗洛里安·里德博士提供的全层CD综合单细胞图谱进行重新分析。我们的研究在野生型（WT）和Areg小鼠中使用了葡聚糖硫酸钠（DSS）诱导的慢性结肠炎模型。此外，还使用了涉及WT和Areg调节性T细胞（Tregs）的CD45RB CD4 T细胞过继转移模型。测定了有无肠道纤维化的CD、Tregs和人肠道肌成纤维细胞（MFs）中AREG的表达。确定了AREG对人肠道MFs增殖/迁移/活化的影响。
狭窄性和非狭窄性CD之间几种类型的细胞存在差异表达。在T细胞中，Tregs占比更大，且在狭窄性CD的狭窄组织中显著增加。尽管DSS诱导的结肠炎在Areg小鼠中更严重，但与WT小鼠相比，其肠道纤维化程度较轻。Areg Tregs的转移导致Rag小鼠的纤维化程度比WT Tregs轻。此外，转化生长因子-β（TGF-β）通过激活Smad3刺激Tregs和人肠道MFs中AREG的表达。
这些发现表明，由TGF-β诱导的Tregs和人肠道MFs来源的AREG在实验性结肠炎以及人类CD患者中放大了肠道纤维化反应。因此，TGF-β-Smad3-AREG途径可能是治疗CD纤维化的潜在治疗靶点。
