Piezo2 is a key mechanoreceptor in lung fibrosis that drives myofibroblast differentiation.

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung disease have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin induced pulmonary fibrosis was assessed. Primary HLFs from non-fibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is upregulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNAseq data showed that Piezo2 is expressed in the pro-fibrotic Cthrc1+ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared to that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression alpha smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents and its presence is key in the differentiation of fibroblasts to the pro-fibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and thus be a novel therapeutic approach to treat pulmonary fibrosis.