PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice
Liran Xu, … , Zuyi Yuan, Shengpeng Wang
Liran Xu, … , Zuyi Yuan, Shengpeng Wang
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e184158. https://doi.org/10.1172/JCI184158.
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Research Article Cell biology Pulmonology

PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn+ myofibroblasts after injury ameliorated lung fibrosis. PIEZO1 was highly expressed in Postn+ myofibroblast and played a vital role in mechanoactivation of Postn+ myofibroblast and development of lung fibrosis. Conditional deletion of Piezo1 in Postn+ myofibroblasts significantly inhibited lung fibrosis by suppressing myofibroblast activation and proliferation. Loss of Piezo1 led to disruption of actin organization and prevention of Yap/Taz nuclear localization, thus shifting the myofibroblasts from a proliferative state into a stressed and apoptotic state. Furthermore, myofibroblast-specific Yap/Taz deletion fully recapitulated the protective phenotypes of myofibroblast-Piezo1–KO mice. These findings show that periostin marks pulmonary myofibroblasts, and that PIEZO1-mediated mechanosensation is essential for myofibroblast activation in the lung. Targeting PIEZO1 in the periostin-expressing cells is a novel therapeutic option to interfere with fibrotic diseases such as IPF .

Authors

Liran Xu, Ting Li, Yapeng Cao, Yu He, Zehua Shao, Siyu Liu, Bianbian Wang, Ailing Su, Huijing Tian, Yongxin Li, Guozheng Liang, Changhe Wang, John Shyy, Ying Xiong, Fangyuan Chen, Jason X.J. Yuan, Junjun Liu, Bin Zhou, Nina Wettschureck, Stefan Offermanns, Yang Yan, Zuyi Yuan, Shengpeng Wang

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Figure 1

Postn+ cell lineage tracing during lung fibrosis.

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Postn+ cell lineage tracing during lung fibrosis. (A) Schematic represen...
(A) Schematic representation showing the genetic strategy for the generation of the Postn-CreERT2; mT/mG mice for lineage tracing. (B) Schematic diagram of the experimental design. Postn-CreERT2; mT/mG mice were challenged to a single intratracheal inhalation of 1 U/kg BLM followed by injection with tamoxifen on 5 consecutive days. The control mice (Postn-CreERT2; mT/mG) without BLM injury (–BLM) were induced by 5 consecutive days tamoxifen and analyzed at day 21 after tamoxifen injection. (C) Representative images of Postn+ lineage GFP+ cells in Postn-CreERT2; mT/mG mice after tamoxifen treatment and BLM challenge. Immunofluorescent staining showing tdTomato and GFP single channels in addition to a merged image. Scale bar: 20 μm. (D and E) Western blot analysis (D) and quantification (E) of the indicated protein levels in the lung of mice at 21 days post bleomycin injury (d.p.i.). n = 4–8. (F) Representative images to identify the Postn+ cells in the mouse lung sections. Antibodies against the stromal markers (α-SMA, Desmin, Pdgfr-β, and Pdgfr-α), endothelial marker CD31, and alveolar type 1 (AT1) cell marker Rage were costained in the lung sections of Postn-CreERT2; mT/mG mice at 21 d.p.i. Scale bar: 20 μm. (G) Quantification of colocalization of the GFP+ cells with α-SMA+, Desmin+, Pdgfr-β+, Pdgfr-α+, CD31+, or Rage+ cells in the lung sections of Postn-CreERT2; mT/mG mice at 21 d.p.i. n = 10. (H) Representative images of Postn expression, which were costained with α-SMA in the lung sections of patients with IPF. Scale bar: 20 μm. n = 8. Shown are mean values ± SEM. Statistical significance was determined by unpaired Student’s t test or the Mann-Whitney U test. ***P < 0.001.