小鼠肠道Cdc42的单基因缺陷导致黏膜炎症并引起隐窝畸形。
Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia.
发表日期：2024 Jan
作者：
Dongsheng Zhang, Wenjuan Tang, Haitao Niu, William Tse, Hai-Bin Ruan, Helmut Dolznig, Thomas Knösel, Friedrich Karl-Heinz, Madeleine Themanns, Jiang Wang, Mingquan Song, Lee Denson, Lukas Kenner, Richard Moriggl, Yi Zheng, Xiaonan Han
来源：
Experimental Hematology & Oncology
摘要：
CDC42控制肠上皮细胞(IEC)干细胞(IESC)分裂。CDC42引发肠道炎症或肿瘤的机制尚不清楚。我们使用炎症性肠病(IBD)、结直肠癌、衰老和IESC损伤模型，确定了在炎症和肿瘤中失去肠道CDC42的情况。收集肠道标本以确定IBD或结直肠癌中CDC42的水平。将Cdc42 floxed小鼠与Villin-Cre、Villin-CreERT2和/或Lgr5-eGFP-IRES-CreERT2，或Bmi1-CreERT2小鼠进行交叉，生成缺失Cdc42的小鼠。辐射、结肠炎、衰老和肠道器官oid用于评估病理性炎症、IESC/祖细胞再生能力和IEC修复的CDC42。我们的研究发现结直肠癌中CDC42的增加与较低的生存率相关；相比之下，在受炎症影响的IBD结肠中发现CDC42水平较低。结肠Cdc42耗竭显著降低了Lgr5+ IESCs，增加了祖细胞的增生，并诱导黏膜炎症，从而导致囊肿发生。结肠Cdc42耗竭明显增强了辐射或化学诱导的结肠炎。Cdc42的耗竭或抑制减少了结肠Lgr5+ IESC的再生。总之，Cdc42的耗竭降低了IESC的再生和IEC的修复，导致黏膜炎症延长。Cdc42的单基因耗竭引发病理性黏膜炎症，可能在衰老背景下导致肠道肿瘤。© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.
CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2, or Bmi1-CreERT2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5+ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5+ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging.© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.