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
View: Text | PDF
Research Article Cell biology Inflammation

Versican regulating viscoelasticity drives pleural fibrosis via mechanotransductive signaling

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

×

Figure 7

Versican reinforced deubiquitination of Smad4 by recruiting USP10 in PMCs.

Options: View larger image (or click on image) Download as PowerPoint
Versican reinforced deubiquitination of Smad4 by recruiting USP10 in PMC...
(A) Ubiquitination of Smad4 was detected by IP in PMCs. (B and C) After transfection with CD44 siRNA for 36 hours, PMCs were cultured in low- or high-viscoelasticity hydrogels for 48 hours. Then PMCs were harvested for immunostaining (B) and qRT-PCR (C) to detect protein and mRNA levels of collagen I and α-SMA. (D and E) After transfection with USP10 siRNA2 for 36 hours, PMCs were cultured with or without recombinant versican (1 μg/mL) for 24 hours; ubiquitination of Smad4 was detected by IP. (F and G) After transfection with USP10 siRNA for 36 hours, PMCs were cultured in low- or high-viscoelasticity hydrogels for 48 hours. Then PMCs were harvested for immunostaining (F) and qRT-PCR (G) to detect protein and mRNA expression of Smad4, collagen I, and α-SMA. (H and I) After transfection with control and USP10 siRNA for 36 hours, PMCs were cultured with or without recombinant versican (1 μg/mL) for 24 hours. Then PMCs were harvested for Western blotting to detect protein expression of fibronectin, collagen I, and α-SMA. (J) Schematic illustration of the mechanisms of versican in PMCs. Data are presented as mean ± SEM. Statistical analyses were performed with 1-way ANOVA. n = 3, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.