Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice.
Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice.
复制标题
DOI：
10.1038/s41392-023-01554-w
复制
发表时间：
2023-08-09
影响因子：
39.3
通讯作者：
Deng, Hongxin
中科院分区：
文献类型：
--
作者：
Liu, Yi;Ji, Yanhong;Jiang, Ruiyi;Fang, Chao;Shi, Gang;Cheng, Lin;Zuo, Yinan;Ye, Yixin;Su, Xiaolan;Li, Junshu;Wang, Huiling;Wang, Yuan;Lin, Yi;Dai, Lei;Zhang, Shuang;Deng, Hongxin
随着年龄的增长，癌症和受损的组织伤口愈合与老年人口的生活质量密切相关。鉴于癌症发病率的增加和全球人口老龄化的趋势，探索老龄化如何损害组织伤口愈合和自发性癌症是非常重要的。在DSS诱导的急性结肠炎和AOM/DSS诱导的结肠炎相关癌症（CAC）的小鼠模型中，我们发现衰老显著降低了肠道伤口愈合和同时CAC的启动，尽管衰老并不影响AOM诱导的散发性非炎性CRC的发生率。从机制上讲，在衰老小鼠的结肠炎微环境中观察到成纤维细胞减少。通过条件性谱系追踪，鉴定了可能来源于肠平滑肌细胞（ISMCs）的成纤维细胞的重要来源，其协调幼年小鼠的肠伤口愈合和CAC起始。然而，来自ISMCs的转化成纤维细胞的数量在衰老小鼠中显著减少，伴随着肠伤口愈合减少和CAC起始减少。离体肠肌层培养实验也证实了年轻小鼠中的ISMCs-成纤维细胞转化和老龄小鼠中这种转化的减少。我们进一步发现ISMCs中雅普/TAZ的激活是ISMCs转化为成纤维细胞所必需的。同时，衰老小鼠肠创伤愈合过程中ISMCs中雅普/TAZ的活化减少。条件性敲低年轻小鼠ISMC中的雅普/TAZ导致结肠炎微环境中的成纤维细胞减少、肠伤口愈合减少和CAC起始减少，与衰老小鼠的表型相似。此外，来自炎症性肠病（IBD）患者的肠样品的数据显示，雅普/TAZ的活化也发生在来自这些患者的ISMC中。总的来说，我们的工作揭示了老化的基质微环境在肠伤口愈合和CAC启动中的重要作用。此外，我们的工作还确定了结肠炎和CAC中涉及的成纤维细胞的潜在来源。
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.
登录
查看更多内容
影响因子：
29.4
作者：
Kobayashi H;Gieniec KA;Lannagan TRM;Wang T;Asai N;Mizutani Y;Iida T;Ando R;Thomas EM;Sakai A;Suzuki N;Ichinose M;Wright JA;Vrbanac L;Ng JQ;Goyne J;Radford G;Lawrence MJ;Sammour T;Hayakawa Y;Klebe S;Shin AE;Asfaha S;Bettington ML;Rieder F;Arpaia N;Danino T;Butler LM;Burt AD;Leedham SJ;Rustgi AK;Mukherjee S;Takahashi M;Wang TC;Enomoto A;Woods SL;Worthley DL
通讯作者：
Worthley DL
影响因子：
64.5
作者：
Kinchen J;Chen HH;Parikh K;Antanaviciute A;Jagielowicz M;Fawkner-Corbett D;Ashley N;Cubitt L;Mellado-Gomez E;Attar M;Sharma E;Wills Q;Bowden R;Richter FC;Ahern D;Puri KD;Henault J;Gervais F;Koohy H;Simmons A
通讯作者：
Simmons A
影响因子：
17.1
作者：
Krall JA;Reinhardt F;Mercury OA;Pattabiraman DR;Brooks MW;Dougan M;Lambert AW;Bierie B;Ploegh HL;Dougan SK;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
5.5
作者：
Albert, Eric J.;Marshall, Jean S.
通讯作者：
Marshall, Jean S.
DOI：
10.1038/nrgastro.2016.59
发表时间：
2016-06
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Hong AW;Meng Z;Guan KL
通讯作者：
Guan KL