Reduced transformation of intestinal smooth muscle cells into fibroblasts inhibit intestinal wound healing and colitis-associated cancer in ageing mice

Although ageing is usually regarded as a high risk of cancer, the relationship between ageing stromal microenvironment and spontaneous cancer initiation is poorly understood. In murine models of DSS-induced colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly inhibit both intestinal wound healing and simultaneous CAC initiation. In young mice, through conditional lineage tracing, a novel and important source of fibroblasts transformed from intestinal smooth muscle cells (ISMCs) was identified during intestinal wound healing, which existed persistently in CAC. We further found that activation of YAP/TAZ in ISMCs is required for their transformation into fibroblasts. However, in ageing intestinal microenvironment, the failure of YAP/TAZ activation in ISMCs led to reduced fibroblast numbers, orchestrating the inhibition of wound healing and simultaneous inhibition of CAC initiation. Collectively, our work revealed an important role of ageing stromal microenvironment in intestinal wound healing and CAC development. Meanwhile, our work also discovered an important source of fibroblasts involved in colitis and CAC. AOM/DSS induced gene expression in young and old murine colorectum was measured at 0, 10 and 21 days. Three independent experiments were performed at each time (0, 10 or 21 days).