Cellular crosstalk of fibroblast–myofibroblast transition in intestinal homeostasis and disease

Fibroblasts are central components of the intestinal microenvironment and can acquire a myofibroblast phenotype through fibroblast-to-myofibroblast transition (FMT), a process linked to increased tissue mechanosensitivity and active extracellular matrix (ECM) remodeling. In this way, FMT participates in normal intestinal homeostasis and repair, but it can also contribute to fibrosis and tumor-associated stromal remodeling when sustained. More importantly, FMT is not a passive process but an active reprogramming event in response to physiological demands or pathological conditions. Its regulation is highly complicated by the temporal and spatial coordination of various intestinal cell types, ultimately determining disease onset and progression. In this context, targeting cellular interaction networks and remodeling the pathological microenvironment may provide opportunities to limit or redirect disease-associated stromal remodeling. In this review, we summarize the key intercellular dialogs that regulate FMT during the onset and progression of intestinal disorders and further analyze their regulatory mechanisms. Moreover, we discuss emerging therapies targeting cellular interaction networks to provide a new framework and research focus for treating inflammatory bowel disease (IBD), intestinal fibrosis, and related tumors.