Titel (eng)

Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

Autor*in

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

Verlag

KEAI Publishing Ltd

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY-NC-ND 4.0 - Creative Commons Namensnennung - Nicht-kommerziell - Keine Bearbeitungen 4.0 International Lizenz.

CC BY-NC-ND 4.0 International

http://creativecommons.org/licenses/by-nc-nd/4.0/

Klassifikation

Cre-Mediated Recombination; Stem-Cells; Colorectal-Cancer; Bowel-Disease; Human Colon; Survival; Differentiation; Proliferation; Tumorigenesis; Complex

Mitglied in der/den Collection(s) (1)