癌症及年龄增长引起的组织修复受损与老年人群的生命质量密切相关。鉴于全球癌症发病率的增加以及人口老龄化趋势，探索年龄对组织修复和自发性癌症的影响非常重要。我们通过DSS诱导的急性结肠炎和AOM/DSS诱导的结肠相关癌症 (CAC) 的鼠模型发现，尽管年龄无影响对AOM诱导的非炎性CRC发病率，但年龄显著降低肠道伤口愈合和同时CAC的发生。机械上观察到，老化小鼠肠炎微环境中的成纤维细胞数量减少。通过条件性谱系追踪，我们发现成纤维细胞的重要来源可能源自肠平滑肌细胞(ISMCs)，在年轻鼠中协调肠道伤口愈合和CAC的发生。然而，在老化小鼠中，由ISMCs转化为成纤维细胞的数量显著减少，同时伴随肠道伤口愈合和CAC的减少。通过体外肠道肌层培养实验证实了ISMCs-成纤维细胞转化在年轻鼠中的发生以及在老化小鼠中的减少。我们进一步发现在ISMCs中激活YAP/TAZ是ISMCs转化为成纤维细胞所必需的。与此同时，我们观察到老化小鼠在肠道伤口愈合过程中ISMCs的YAP/TAZ激活减少。在年轻小鼠的ISMCs中条件性沉默YAP/TAZ结果显示成纤维细胞在肠炎微环境中减少，肠道伤口愈合和CAC的发生也减少，与老化小鼠的表型相似。此外，来自炎症性肠病(IBD)患者的肠道样本数据显示，在这些患者的ISMCs中也存在YAP/TAZ的激活。综上所述，我们的研究揭示了老化的基质微环境在肠道伤口愈合和CAC发生中的重要作用。此外，我们的研究还鉴定了有关结肠炎和CAC的成纤维细胞的潜在来源。© 2023. 西南医科大学华西医院。

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.