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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE143693 | GEO | 2023/08/21

REPOSITORIES: GEO

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Project description:Purpose: PKM2-mediated metabolic switch to aerobic glycolysis plays a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestinal homeostasis. Here we investigated whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental murine colitis. Methods: Colonoscopic biopsies from the Crohn’s disease (CD) and ulcerative colitis (UC) patients (10 each) were analyzed for PKM2 expression. We also generated intestinal epithelial-specific Pkm2 knockout mice and employed them to examine PKM2 function. Mouse intestinal inflammation was induced with dextran sulfate sodium (DSS) in drinking water. Disease phenotypes were investigated by mouse survival, body weight, colon length and analysis of immune cell infiltration in colon, intestinal epithelial cell gene profiling and signal pathway. Results: Intestinal epithelial PKM2 level in UC and CD patients was significantly decreased compared to that from non-inflamed intestinal epithelium. Similar reduction of intestinal epithelial PKM2 was observed in mice with experimental colitis. Supporting the notion that PKM2 serves as a safeguard against colitis, intestinal epithelial-specific Pkm2-deficient (Pkm2-/-) mice displayed a severer intestinal inflammation, companying with shortened colon, disruption of epithelial tight junction, higher permeability, elevation of inflammatory cytokines and immune cell infiltration, compared with wild-type mice. Gene profiling and western blot analysis indicated that cell survival signaling, particularly the Akt/β-catenin pathways, were downregulated in Pkm2-/- mice. Functional assay using mouse primary colonic epithelial cells confirmed that Pkm2 reduction decreased proliferation and migration of epithelial cells, while enhanced expression of Pkm2 was associated with increased transcriptional activity of β-catenin. Moreover, increasing mouse intestinal epithelial Pkm2 expression via delivery of Pkm2-expressing plasmid attenuated DSS-induced experimental colitis. Conclusions: Intestinal epithelial PKM2, through activating Wnt/β-catenin signaling, induces a strong proliferative and migratory response that increases cell survival and wound healing under colitic condition.

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

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