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Title (en)
Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia
Language
English
Description (en)
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.
Keywords (en)
Cre-Mediated Recombination; Stem-Cells; Colorectal-Cancer; Bowel-Disease; Human Colon; Survival; Differentiation; Proliferation; Tumorigenesis; Complex
DOI
10.1016/j.gendis.2022.11.024
Author of the digital object
Dongsheng Zhang  (Case Western Reserve University / Cincinnati Children's Hospital Medical Center)
Xiaonan Han  (Case Western Reserve University)
Yi Zheng  (Cincinnati Children's Hospital Medical Center)
Richard Moriggl  (Ludwig Boltzmann Institute for Cancer Research / University of Veterinary Medicine Vienna)
Lukas Kenner  (Medical University of Vienna)
Lee Denson  (Cincinnati Children's Hospital Medical Center)
Mingquan Song  (Qingdao University)
Jiang Wang  (University of Cincinnati)
Madeleine Themanns  (University of Veterinary Medicine Vienna)
Friedrich Karl-Heinz  (University Hospital Jena)
Thomas Knösel  (Ludwig-Maximilians-University Munich)
Helmut Dolznig  (Medical University of Vienna)
Wenjuan Tang  (Cincinnati Children's Hospital Medical Center / Children's Hospital of Fudan University)
Haitao Niu  (Jinan University / Chinese Academy of Medical Science and Peking Union Medical College)
William Tse  (Case Western Reserve University)
Hai-Bin Ruan  (University of Minnesota Medical School)
Format
application/pdf
Size
1.1 MB
Licence Selected
CC BY-NC-ND 4.0 International
Type of publication
Article
Name of Publication (en)
Genes & Diseases
Pages or Volume
17
Volume
11
Number
1
From Page
413
To Page
429
Publisher
KEAI Publishing Ltd
Publication Date
2023