Intercellular contact is sufficient to drive fibroblast-to-myofibroblast transitions

Fibroblast cells play a key role in maintaining the extracellular matrix. During wound healing, fibroblasts differentiate into highly contractile myofibroblasts, which secrete extracellular matrix proteins, such as collagen, to facilitate tissue repair. Under normal conditions, myofibroblasts undergo programmed cell death after healing to prevent excessive scar formation. However, in diseases such as fibrosis, myofibroblasts remain active even after the wound is closed, resulting in excessive collagen buildup and a stiff, fibrotic matrix. The reasons for the persistence of myofibroblasts in fibrosis are not well understood. Here, we show the existence of a mechanism where direct physical contact between a fibroblast and a myofibroblast is sufficient for fibroblasts to transition into myofibroblasts. We demonstrate that the fibroblast-myofibroblast transition can occur even in the absence of known biochemical cues, such as growth factor activation or mechanical cues from a stiff, fibrotic matrix. Furthermore, we demonstrate that contact-based fibroblast-myofibroblast activation can be inhibited by the Gαq/11/14 inhibitor FR900359, which prevents the formation of myofibroblasts. These findings provide new insights into the persistence of the myofibroblast phenotype and highlight potential approaches to regulate the fibroblast-to-myofibroblast transition.NEW & NOTEWORTHY This study uncovers a novel mechanism of fibroblast-to-myofibroblast transition (FMT) driven by cell-cell contact. Myofibroblast-fibroblast contact elevates cytoskeletal tension in the fibroblast, which in turn drives transition via activation of the GqGPCR signaling pathway. This process occurs independently of exogenous biochemical cues or stiff matrices. Emphasizing the central role of cytoskeletal stress in FMT, these findings reveal a mechanoregulated pathway, opening potential new avenues to investigate myofibroblast persistence.