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Versican regulating viscoelasticity drives pleural fibrosis via mechanotransductive signaling
Zi-Heng Jia, Xin-Liang He, Xiao-Lin Cui, Qian Li, Pei-Pei Cheng, Li-Qin Zhao, Shu-Yi Ye, Shi-He Hu, Chen-Yue Lian, He-De Zhang, Li-Mei Liang, Lin-Jie Song, Fan Yu, Liang Xiong, Fei Xiang, Xiaorong Wang, Meng Wang, Xiyong Dai, Hong Ye, Wan-Li Ma
Zi-Heng Jia, Xin-Liang He, Xiao-Lin Cui, Qian Li, Pei-Pei Cheng, Li-Qin Zhao, Shu-Yi Ye, Shi-He Hu, Chen-Yue Lian, He-De Zhang, Li-Mei Liang, Lin-Jie Song, Fan Yu, Liang Xiong, Fei Xiang, Xiaorong Wang, Meng Wang, Xiyong Dai, Hong Ye, Wan-Li Ma
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Research Article Cell biology Inflammation

Versican regulating viscoelasticity drives pleural fibrosis via mechanotransductive signaling

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Abstract

Extracellular matrix (ECM) disorder was believed to result from fibrosis, but it has recently been recognized that fibrotic ECM initiates a self-reinforcing circuit and contributes to the development of fibrosis. Versican, an ECM component, participates in cell-ECM interaction and ECM regeneration. In pleura, versican is primarily derived from pleural mesothelial cells (PMCs). However, the role and mechanism of versican in pleural fibrosis has remained unknown. In this study, versican and versican-mediated pleural viscoelasticity were found to be elevated in both human and murine pleural fibrotic tissues. Versican knockdown by shRNA prevented increases in viscoelasticity as well as pleural fibrosis. High levels of versican and viscoelasticity promoted mesothelial-mesenchymal transition in PMCs. Mechanistically, increased viscoelasticity induced pleural fibrosis through the CD44/USP10/Smad4 mechanotransduction pathway. In conclusion, these results revealed that excessive versican in fibrotic pleural ECM enhanced ECM viscoelasticity and consequently promoted progression of pleural fibrosis.

Authors

Zi-Heng Jia, Xin-Liang He, Xiao-Lin Cui, Qian Li, Pei-Pei Cheng, Li-Qin Zhao, Shu-Yi Ye, Shi-He Hu, Chen-Yue Lian, He-De Zhang, Li-Mei Liang, Lin-Jie Song, Fan Yu, Liang Xiong, Fei Xiang, Xiaorong Wang, Meng Wang, Xiyong Dai, Hong Ye, Wan-Li Ma

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Figure 4

Loss of versican reduced viscoelasticity of fibrotic pleura.

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Loss of versican reduced viscoelasticity of fibrotic pleura.
(A) Schemat...
(A) Schematic of rheometry analysis of fresh pleural tissues. (B) Rheometry analysis of the storage modulus in control and fibrotic pleura. (C) The loss tangent (viscoelasticity) in control and fibrotic pleura. (D) Stress relaxation curves in pleura samples from control and patient groups. Norm., normalized. (E) Stress was normalized to the initial stress and depicted as τ1/2 (the timescale at which the stress is relaxed to half its original value). (F) Pleural tissues were taken from patients with pleural fibrosis and controls. Shear viscosity was detected and corresponding curves were made. (G) Bar graphs showing relative fold-changes in viscosity with shear rate at 10 (s–1). (B, C, E, and G) Data are presented as mean ± SEM. Statistical analyses were performed with unpaired Student’s t tests. n = 5, *P < 0.05. (H–M) Mouse pleural fibrosis model was induced by intrapleural injection of bleomycin plus carbon particles. Lentivirus expressing shRNA directed against versican (VCAN) shRNA or scrambled sequence shRNA was administrated by intrapleural injection at a dose of 2 × 106 TU on days 4, 7, and 10. After a lung function test, all mice were euthanized at day 21, and then tissues were taken for analysis. (H) Rheometry analysis of the storage modulus. (I) The loss tangent (viscoelasticity) in mouse pleura. (J) Stress relaxation curves in mouse pleura. (K) Stress was normalized to the initial stress and depicted as τ1/2 (the timescale at which the stress is relaxed to half its original value). (L) Shear viscosity was detected and corresponding curves were made. (M) Bar graphs showing relative fold-changes in viscosity with shear rate at 10 (s–1). (H, I, K, and M) Data are presented as mean ± SEM. Statistical analyses were performed with 1-way ANOVA. n = 4, **P < 0.01, ***P < 0.001.

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