Piezo2 Is a Key Mechanoreceptor in Lung Fibrosis that Drives Myofibroblast Differentiation

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases 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, 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) was investigated. Human samples from patients with IPF and mouse tissue from bleomycin-induced pulmonary fibrosis were assessed. Primary HLFs from nonfibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression was up-regulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, analysis of published single-cell RNA-sequencing data showed that Piezo2 was expressed in the profibrotic collagen triple helix repeat containing 1 (Cthrc1)⁺ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared with that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression α-smooth muscle actin and fibronectin in HLFs. Piezo2 expression was elevated in fibrotic lung disease in both patients and rodents, and its presence was key in the differentiation of fibroblasts to the profibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis.