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Theranostics 2019; 9(17):4993-5008. doi:10.7150/thno.35665 This issue Cite

Research Paper

Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis

Siyi Li*, Chao Li*, Yiting Zhang, Xiu He, Xi Chen, Xinning Zeng, Fangwei Liu, Ying Chen, Jie Chen✉

Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, PR China.
*Equal contribution to this study.

✉ Corresponding author: Jie Chen e-mail: jchenedu.cn, Tel: 86 24 31939079

Citation:
Li S, Li C, Zhang Y, He X, Chen X, Zeng X, Liu F, Chen Y, Chen J. Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis. Theranostics 2019; 9(17):4993-5008. doi:10.7150/thno.35665. https://www.thno.org/v09p4993.htm
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Abstract

Graphic abstract

Silicosis is pneumoconiosis of the lung, usually resulting from prolonged exposure to crystalline silica (CS). The hallmark of silicosis is excessive extracellular matrix (ECM) deposition produced by activated fibroblasts. Recent work demonstrated that excessive ECM-forming mechanical cues play an essential role in promoting fibroblast activation and perpetuating fibrotic pathologies. However, the detailed molecular mechanism still needs to be uncovered.

Methods: NIH-3T3 fibroblasts were cultured on either 1 kappa (soft) or 60 kappa (stiff) gel-coated coverslips. A series of knockdown and reverse experiments in vitro were performed to establish the signaling for mechanics-induced fibroblast activation. An experimental model of silicosis was established by one-time intratracheal instillation of CS suspension. The cluster of differentiation 44 (CD44) antibody (IM7), dihydrotanshinone I (DHI) and verteporfin (VP) were used to explore the effect of CD44-RhoA-YAP signaling blockade on mechanics-induced fibroblast activation and CS-induced pulmonary fibrosis.

Results: Matrix stiffness could induce nuclear translocation of the Yes-associated protein (YAP) through CD44 in fibroblasts. This effect required RhoA activity and F-actin cytoskeleton polymerization but was independent of Hippo pathway kinases, Mst 1 and Lats 1, forming CD44-RhoA-YAP signaling pathway. Pharmacological upstream blocking by CD44 antibody or downstream blockade of YAP by DHI or VP could attenuate fibroblast migration, invasion, proliferation, and collagen deposition. Furthermore, CD44-RhoA-YAP signaling blockade could alleviate CS-induced fibrosis and improve pulmonary function in vivo.

Conclusion: CD44-RhoA-YAP signaling mediates mechanics-induced fibroblast activation. Targeting this pathway could ameliorate crystalline silica-induced silicosis and provide a potential therapeutic strategy to mitigate fibrosis.

Keywords: silicosis therapy, mechanics, fibroblast activation, Yes-associated protein

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APA
Li, S., Li, C., Zhang, Y., He, X., Chen, X., Zeng, X., Liu, F., Chen, Y., Chen, J. (2019). Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis. Theranostics, 9(17), 4993-5008. https://doi.org/10.7150/thno.35665.

ACS
Li, S.; Li, C.; Zhang, Y.; He, X.; Chen, X.; Zeng, X.; Liu, F.; Chen, Y.; Chen, J. Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis. Theranostics 2019, 9 (17), 4993-5008. DOI: 10.7150/thno.35665.

NLM
Li S, Li C, Zhang Y, He X, Chen X, Zeng X, Liu F, Chen Y, Chen J. Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis. Theranostics 2019; 9(17):4993-5008. doi:10.7150/thno.35665. https://www.thno.org/v09p4993.htm

CSE
Li S, Li C, Zhang Y, He X, Chen X, Zeng X, Liu F, Chen Y, Chen J. 2019. Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis. Theranostics. 9(17):4993-5008.

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