BPS2026 – Intercellular contact is sufficient to drive fibroblast to myofibroblast transitions

Fibroblasts are essential for maintaining the extracellular matrix and facilitating wound repair by differentiating into contractile myofibroblasts that secrete collagen. Normally, myofibroblasts undergo programmed cell death after healing to prevent excessive scarring. In fibrosis, however, their persistent activation drives collagen accumulation and matrix stiffening. Despite therapies targeting matrix stiffness and canonical biochemical pathways (such as TGFβ signaling), diseases like idiopathic pulmonary fibrosis continue to progress, suggesting additional mechanisms are involved. Here, we identify a previously unrecognized mechanism in which direct physical contact between fibroblasts and myofibroblasts is sufficient to trigger fibroblast-to-myofibroblast transition (FMT), even in the absence of a stiff matrix or exogenous signaling factors. We show that contractility (M ii ) in fibroblasts rises significantly upon contact with a myofibroblast, precedes phenotype change and mechanically activates phospholipase C (PLC), driving the transition. This contact mediated activation is blocked by the Gαq/11/14 inhibitor FR900359, establishing GqGPCR signaling as a critical mediator. Strikingly, TGFβ inhibitors also act on myofibroblasts in soft matrices (0.3kPa) by rapidly reducing cytoskeletal tension, underscoring tension as a central regulator of FMT. These findings broaden the understanding of fibrosis by demonstrating that myofibroblast activation can occur through cell-cell interactions and intrinsic mechanotransduction, not only through external mechanical or biochemical cues. By identifying GqGPCR signaling as a key pathway, our work highlights cytoskeletal tension as a unifying mechano-therapeutic target and opens new avenues for interventions aimed at halting fibrosis progression.