Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia
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 inflam...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2024-01-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304222003300 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dongsheng Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T15:20:07Z |
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| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2025-03-22T04:28:28Z |
| publishDate | 2024-01-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-b0fc0e6ade90487d8ef2c302ccd35c042024-04-28T04:50:56ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422024-01-01111413429Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasiaDongsheng Zhang0Wenjuan Tang1Haitao Niu2William Tse3Hai-Bin Ruan4Helmut Dolznig5Thomas Knösel6Friedrich Karl-Heinz7Madeleine Themanns8Jiang Wang9Mingquan Song10Lee Denson11Lukas Kenner12Richard Moriggl13Yi Zheng14Xiaonan Han15Division 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; Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH 44106, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USADivision of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA; Children's Hospital of Fudan University, Shanghai 201102, ChinaSchool of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Laboratory Animal Science (ILAS), Chinese Academy of Medical Science (CAMS) and Peking Union Medical College (PUMC), Beijing 100006, ChinaDivision 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; Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH 44106, USADepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MI 55455, USAInstitute of Medical Genetics, Medical University of Vienna, Vienna 1040, AustriaInstitute of Pathology, Ludwig-Maximilians-University Munich, Munich 80539, GermanyInstitute of Biochemistry II, University Hospital Jena, Jena 07743, GermanyLaboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna 1210, AustriaDepartment of Pathology, University of Cincinnati, Cincinnati, OH 45221, USADepartment of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266005, ChinaDivision of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USADepartment of Pathology, Medical University of Vienna, Vienna 1040, AustriaLudwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria; Medical University of Vienna, Vienna 1040, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna 1210, AustriaDivision of Experimental Hematology, CCHMC, Cincinnati, OH 45229, USADivision 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; Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH 44106, USA; Corresponding author. 2500 Metrohealth Dr, Rammelkamp 461, Cleveland, OH 44109, USA.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.http://www.sciencedirect.com/science/article/pii/S2352304222003300Cell division cycle 42 (CDC42)ColitisColorectal cancer (CRC)Inflammatory bowel diseases (IBD)Intestinal epithelial cell (IEC)Intestinal epithelial stem cell (IESC) |
| spellingShingle | 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 Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia Genes and Diseases Cell division cycle 42 (CDC42) Colitis Colorectal cancer (CRC) Inflammatory bowel diseases (IBD) Intestinal epithelial cell (IEC) Intestinal epithelial stem cell (IESC) |
| title | Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| title_full | Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| title_fullStr | Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| title_full_unstemmed | Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| title_short | Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| title_sort | monogenic deficiency in murine intestinal cdc42 leads to mucosal inflammation that induces crypt dysplasia |
| topic | Cell division cycle 42 (CDC42) Colitis Colorectal cancer (CRC) Inflammatory bowel diseases (IBD) Intestinal epithelial cell (IEC) Intestinal epithelial stem cell (IESC) |
| url | http://www.sciencedirect.com/science/article/pii/S2352304222003300 |
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