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

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

Physiology

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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.

Original language	English (US)
Pages (from-to)	413-429
Number of pages	17
Journal	Genes and Diseases
Volume	11
Issue number	1
DOIs	https://doi.org/10.1016/j.gendis.2022.11.024
State	Published - Jan 2024

Bibliographical note

Funding Information:
This work was supported by NIDDK R01 (No. R01 DK123299 ) (X.H.) and MHMC/CWRU start-up (X.H.). R.M. was supported by a private cancer metabolism grant donation from Liechtenstein and the Austrian Science Fund (FWF) (No. SFB F4707 and SFB-F06105 ).

Publisher Copyright:
© 2023 Chongqing Medical University

Keywords

Cell division cycle 42 (CDC42)
Colitis
Colorectal cancer (CRC)
Inflammatory bowel diseases (IBD)
Intestinal epithelial cell (IEC)
Intestinal epithelial stem cell (IESC)
Irradiation

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.gendis.2022.11.024

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Zhang, D., Tang, W., Niu, H., Tse, W., Ruan, H. B., Dolznig, H., Knösel, T., Karl-Heinz, F., Themanns, M., Wang, J., Song, M., Denson, L., Kenner, L., Moriggl, R., Zheng, Y., & Han, X. (2024). Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia. Genes and Diseases, 11(1), 413-429. https://doi.org/10.1016/j.gendis.2022.11.024

Zhang, D, Tang, W, Niu, H, Tse, W, Ruan, HB, Dolznig, H, Knösel, T, Karl-Heinz, F, Themanns, M, Wang, J, Song, M, Denson, L, Kenner, L, Moriggl, R, Zheng, Y & Han, X 2024, 'Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia', Genes and Diseases, vol. 11, no. 1, pp. 413-429. https://doi.org/10.1016/j.gendis.2022.11.024

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title = "Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia",

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-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 = "Cell division cycle 42 (CDC42), Colitis, Colorectal cancer (CRC), Inflammatory bowel diseases (IBD), Intestinal epithelial cell (IEC), Intestinal epithelial stem cell (IESC), Irradiation",

author = "Dongsheng Zhang and Wenjuan Tang and Haitao Niu and William Tse and Ruan, {Hai Bin} and Helmut Dolznig and Thomas Kn{\"o}sel and Friedrich Karl-Heinz and Madeleine Themanns and Jiang Wang and Mingquan Song and Lee Denson and Lukas Kenner and Richard Moriggl and Yi Zheng and Xiaonan Han",

note = "Funding Information: This work was supported by NIDDK R01 (No. R01 DK123299 ) (X.H.) and MHMC/CWRU start-up (X.H.). R.M. was supported by a private cancer metabolism grant donation from Liechtenstein and the Austrian Science Fund (FWF) (No. SFB F4707 and SFB-F06105 ). Publisher Copyright: {\textcopyright} 2023 Chongqing Medical University",

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T1 - Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

AU - Zhang, Dongsheng

AU - Tang, Wenjuan

AU - Niu, Haitao

AU - Tse, William

AU - Ruan, Hai Bin

AU - Dolznig, Helmut

AU - Knösel, Thomas

AU - Karl-Heinz, Friedrich

AU - Themanns, Madeleine

AU - Wang, Jiang

AU - Song, Mingquan

AU - Denson, Lee

AU - Kenner, Lukas

AU - Moriggl, Richard

AU - Zheng, Yi

AU - Han, Xiaonan

N1 - Funding Information: This work was supported by NIDDK R01 (No. R01 DK123299 ) (X.H.) and MHMC/CWRU start-up (X.H.). R.M. was supported by a private cancer metabolism grant donation from Liechtenstein and the Austrian Science Fund (FWF) (No. SFB F4707 and SFB-F06105 ). Publisher Copyright: © 2023 Chongqing Medical University

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

KW - Cell division cycle 42 (CDC42)

KW - Colitis

KW - Colorectal cancer (CRC)

KW - Inflammatory bowel diseases (IBD)

KW - Intestinal epithelial cell (IEC)

KW - Intestinal epithelial stem cell (IESC)

KW - Irradiation

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DO - 10.1016/j.gendis.2022.11.024

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AN - SCOPUS:85146464417

SN - 2352-4820

VL - 11

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JO - Genes and Diseases

JF - Genes and Diseases

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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