Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice
Abstract Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneou...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01554-w |
| _version_ | 1797451328844201984 |
|---|---|
| author | Yi Liu Yanhong Ji Ruiyi Jiang Chao Fang Gang Shi Lin Cheng Yinan Zuo Yixin Ye Xiaolan Su Junshu Li Huiling Wang Yuan Wang Yi Lin Lei Dai Shuang Zhang Hongxin Deng |
| author_facet | Yi Liu Yanhong Ji Ruiyi Jiang Chao Fang Gang Shi Lin Cheng Yinan Zuo Yixin Ye Xiaolan Su Junshu Li Huiling Wang Yuan Wang Yi Lin Lei Dai Shuang Zhang Hongxin Deng |
| author_sort | Yi Liu |
| collection | DOAJ |
| description | Abstract Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC. |
| first_indexed | 2024-03-09T14:53:06Z |
| format | Article |
| id | doaj.art-3f9fd583066344808febb66bc0e8aa63 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-09T14:53:06Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-3f9fd583066344808febb66bc0e8aa632023-11-26T14:21:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-08-018111710.1038/s41392-023-01554-wReduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing miceYi Liu0Yanhong Ji1Ruiyi Jiang2Chao Fang3Gang Shi4Lin Cheng5Yinan Zuo6Yixin Ye7Xiaolan Su8Junshu Li9Huiling Wang10Yuan Wang11Yi Lin12Lei Dai13Shuang Zhang14Hongxin Deng15Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Gastrointestinal Surgery, West China Hospital and State Key Laboratory of Biotherapy, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityRespiratory Microbiome Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for BiotherapyDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityAbstract Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC.https://doi.org/10.1038/s41392-023-01554-w |
| spellingShingle | Yi Liu Yanhong Ji Ruiyi Jiang Chao Fang Gang Shi Lin Cheng Yinan Zuo Yixin Ye Xiaolan Su Junshu Li Huiling Wang Yuan Wang Yi Lin Lei Dai Shuang Zhang Hongxin Deng Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice Signal Transduction and Targeted Therapy |
| title | Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice |
| title_full | Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice |
| title_fullStr | Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice |
| title_full_unstemmed | Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice |
| title_short | Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice |
| title_sort | reduced smooth muscle fibroblasts transformation potentially decreases intestinal wound healing and colitis associated cancer in ageing mice |
| url | https://doi.org/10.1038/s41392-023-01554-w |
| work_keys_str_mv | AT yiliu reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT yanhongji reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT ruiyijiang reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT chaofang reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT gangshi reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT lincheng reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT yinanzuo reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT yixinye reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT xiaolansu reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT junshuli reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT huilingwang reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT yuanwang reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT yilin reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT leidai reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT shuangzhang reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice AT hongxindeng reducedsmoothmusclefibroblaststransformationpotentiallydecreasesintestinalwoundhealingandcolitisassociatedcancerinageingmice |