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

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

doi:10.1016/j.gendis.2022.11.024

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

Genes Dis. 2023 Jan 2;11(1):413-429. doi: 10.1016/j.gendis.2022.11.024. eCollection 2024 Jan.

Authors

Dongsheng Zhang^{1

2

3}, Wenjuan Tang^{3

4}, Haitao Niu^{5

6}, William Tse^{1

2}, Hai-Bin Ruan⁷, Helmut Dolznig⁸, Thomas Knösel⁹, Friedrich Karl-Heinz¹⁰, Madeleine Themanns¹¹, Jiang Wang¹², Mingquan Song¹³, Lee Denson³, Lukas Kenner¹⁴, Richard Moriggl^{15

16

17}, Yi Zheng¹⁸, Xiaonan Han^{1

2}

Affiliations

¹ Division of Hematology and Oncology, Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU), School of Medicine, Cleveland, OH 44109, USA.
² Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH 44106, USA.
³ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA.
⁴ Children's Hospital of Fudan University, Shanghai 201102, China.
⁵ School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
⁶ Laboratory Animal Science (ILAS), Chinese Academy of Medical Science (CAMS) and Peking Union Medical College (PUMC), Beijing 100006, China.
⁷ Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MI 55455, USA.
⁸ Institute of Medical Genetics, Medical University of Vienna, Vienna 1040, Austria.
⁹ Institute of Pathology, Ludwig-Maximilians-University Munich, Munich 80539, Germany.
¹⁰ Institute of Biochemistry II, University Hospital Jena, Jena 07743, Germany.
¹¹ Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna 1210, Austria.
¹² Department of Pathology, University of Cincinnati, Cincinnati, OH 45221, USA.
¹³ Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266005, China.
¹⁴ Department of Pathology, Medical University of Vienna, Vienna 1040, Austria.
¹⁵ Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria.
¹⁶ Medical University of Vienna, Vienna 1040, Austria.
¹⁷ Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna 1210, Austria.
¹⁸ Division of Experimental Hematology, CCHMC, Cincinnati, OH 45229, USA.

Abstract

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-CreER^T2 and/or Lgr5-eGFP-IRES-CreER^T2, or Bmi1-CreER^T2 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: Cell division cycle 42 (CDC42); Colitis; Colorectal cancer (CRC); Inflammatory bowel diseases (IBD); Intestinal epithelial cell (IEC); Intestinal epithelial stem cell (IESC); Irradiation.