PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice
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
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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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 2

Postn+ cell ablation mitigates BLM-induced pulmonary fibrosis in mice.

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Postn+ cell ablation mitigates BLM-induced pulmonary fibrosis in mice. (...
(A) Schematic representation showing the genetic strategy for generation of the Postn-CreERT2; R26-iDTR mice for ablation of Postn+ cells. (B) Schematic diagram of the experimental design. Postn-CreERT2; R26-iDTR were challenged to a single intratracheal inhalation of BLM followed by injection with tamoxifen on 5 consecutive days. Then the mice were injected with DT or vehicle for 7 consecutive days. After 7 days, the control (R26-iDTR) and Postn-CreERT2; R26-iDTR mice were euthanized for subsequent analysis. (C) Real-time qPCR analysis of iDTR mRNA expression levels in the lung of Postn-CreERT2; R26-iDTR and control mice. n = 4–5. (D and E) Survival percentage (D) and body weight change (E) of Postn-CreERT2; R26-iDTR and control mice. n = 5. (F) (left) Representative images of H&E, Sirius Red, and Masson staining in the lung sections of Postn-CreERT2; R26-iDTR mice after Postn+ cell ablation. (right) Quantification of the Ashcroft score, Sirius red fibrosis and Masson fibrosis area. (Scale bar: 1 mm, top; 100 μm, bottom). n = 5. (G) Representative images of Postn and α-SMA expression and quantification of α-SMA+ and Postn+ area in the lung sections of Postn-CreERT2; R26-iDTR mice after Postn+ cells ablation. Scale bar:100 μm. n = 5. (H) Hydroxyproline content in the lung of ablated and control mice after BLM challenge. n = 5. (I) Real-time qPCR analysis of Acta2, Col1a1, Postn, Fn1, Col3a1, and Tgfb1 mRNA expression levels in the lungs of Postn-CreERT2; R26-iDTR mice after the Postn+ cells ablation. n = 5. Shown are mean values ± SEM. Statistical significance was determined by the Mann-Whitney U test. **P < 0.01.