Theranostics 2021; 11(15):7262-7275. doi:10.7150/thno.49116 This issue Cite

Research Paper

Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver

Yongjie Zhou1, Hongjie Ji3, Qing Xu1, Xiaoyun Zhang4, Xiaoyue Cao1, Yuwei Chen1, Mingyang Shao1, Zhenru Wu1, Jie Zhang5, Changli Lu2, Jiayin Yang4✉, Yujun Shi1✉, Hong Bu1,2

1. Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
3. School of Bioscience and Technology, Weifang Medical University, Weifang 261042, China.
4. Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
5. Core Facility of West China Hospital, Sichuan University, Chengdu 610041, China.

Citation:
Zhou Y, Ji H, Xu Q, Zhang X, Cao X, Chen Y, Shao M, Wu Z, Zhang J, Lu C, Yang J, Shi Y, Bu H. Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver. Theranostics 2021; 11(15):7262-7275. doi:10.7150/thno.49116. https://www.thno.org/v11p7262.htm
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Abstract

Graphic abstract

Rationale: Congenital biliary atresia (BA) is a destructive obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. However, the cause of BA is largely unknown.

Methods: We explored the cell junctions and polarity complexes in early biopsy BA livers by immunofluorescence staining and western blot. Cdc42, as a key cell junction and polarity regulator, was found dramatically decreased in BA livers. Therefore, in order to investigate the role of Cdc42 in BA development, we constructed liver-specific and tamoxifen induced cholangiocyte-specific Cdc42 deleted transgenic mice. We further evaluated the role of bile acid in aggravating biliary damage in Cdc42 insufficient mouse liver.

Results: We found a dramatic defect in the assembly of cell junctions and polarity complexes in both cholangiocytes and hepatocytes in BA livers. This defect was characterized by the disordered location of cell junction proteins, including ZO1, β-catenin, E-cadherin and claudin-3. Cdc42 and its active form, Cdc42-GTP, which serves as a small Rho GTPase to orchestrate the assembly of polarity complexes with Par6/Par3/αPKC, were substantially reduced in BA livers. Selective Cdc42 deficiency in fetal mouse cholangiocytes resulted in histological changes similar to those found in human BA livers, including obstruction in both the intra- and extrahepatic bile ducts, epithelial atrophy, and the disruption of cell junction and polarity complexes. A reduction in bile acids notably improved the histology and serological indices in Cdc42-mutant mice.

Conclusion: Our results illustrate that BA is closely correlated with the impaired assembly of cell junction and polarity complexes in liver cells, which is likely caused by Cdc42 insufficiency and aggravated by bile acid corrosion.

Keywords: Cdc42, biliary atresia, epithelial junction, cell polarity, bile acids


Citation styles

APA
Zhou, Y., Ji, H., Xu, Q., Zhang, X., Cao, X., Chen, Y., Shao, M., Wu, Z., Zhang, J., Lu, C., Yang, J., Shi, Y., Bu, H. (2021). Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver. Theranostics, 11(15), 7262-7275. https://doi.org/10.7150/thno.49116.

ACS
Zhou, Y.; Ji, H.; Xu, Q.; Zhang, X.; Cao, X.; Chen, Y.; Shao, M.; Wu, Z.; Zhang, J.; Lu, C.; Yang, J.; Shi, Y.; Bu, H. Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver. Theranostics 2021, 11 (15), 7262-7275. DOI: 10.7150/thno.49116.

NLM
Zhou Y, Ji H, Xu Q, Zhang X, Cao X, Chen Y, Shao M, Wu Z, Zhang J, Lu C, Yang J, Shi Y, Bu H. Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver. Theranostics 2021; 11(15):7262-7275. doi:10.7150/thno.49116. https://www.thno.org/v11p7262.htm

CSE
Zhou Y, Ji H, Xu Q, Zhang X, Cao X, Chen Y, Shao M, Wu Z, Zhang J, Lu C, Yang J, Shi Y, Bu H. 2021. Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver. Theranostics. 11(15):7262-7275.

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