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Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice

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收录情况： ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：领军期刊

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机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, The People’s Republic ofChina [2]Department of Gastrointestinal Surgery, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, 610041 Chengdu, Sichuan, The People’sRepublic of China [3]Respiratory Microbiome Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital,Sichuan University, 610041 Chengdu, Sichuan, The People’s Republic of China [4]Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University andCollaborative Innovation Center for Biotherapy, 610041 Chengdu, Sichuan, The People’s Republic of China

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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.© 2023. West China Hospital, Sichuan University.

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出版当年[2023]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区细胞生物学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区细胞生物学

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第一作者机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, The People’s Republic ofChina

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