Stellate cell-specific adhesion molecule protocadherin 7 regulates sinusoidal contraction

Author:

Carter James K.1ORCID,Tsai Ming-Chao12ORCID,Venturini Nicholas1ORCID,Hu Jiangting3,Lemasters John J.34ORCID,Torres Martin Miguel5,Sia Daniela1,Wang Shuang1ORCID,Lee Youngmin A.16,Friedman Scott L.1ORCID

Affiliation:

1. Department of Internal Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA

2. Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

3. Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

4. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA

5. Genetics Department, Clinical Genomics Unit, Clinical Genetics Service, Germans Trias i Pujol University Hospital, Barcelona, Spain

6. Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Abstract

Background and Aims: Sustained inflammation and hepatocyte injury in chronic liver disease activate HSCs to transdifferentiate into fibrogenic, contractile myofibroblasts. We investigated the role of protocadherin 7 (PCDH7), a cadherin family member not previously characterized in the liver, whose expression is restricted to HSCs. Approach and Results: We created a PCDH7fl/fl mouse line, which was crossed to lecithin retinol acyltransferase-Cre mice to generate HSC-specific PCDH7 knockout animals. HSC contraction in vivo was tested in response to the HSC-selective vasoconstrictor endothelin-1 using intravital multiphoton microscopy. To establish a PCDH7 null HSC line, cells were isolated from PCDH7fl/fl mice and infected with adenovirus-expressing Cre. Hepatic expression of PCDH7 was strictly restricted to HSCs. Knockout of PCDH7 in vivo abrogated HSC-mediated sinusoidal contraction in response to endothelin-1. In cultured HSCs, loss of PCDH7 markedly attenuated contractility within collagen gels and led to altered gene expression in pathways governing adhesion and vasoregulation. Loss of contractility in PCDH7 knockout cells was impaired Rho-GTPase signaling, as demonstrated by altered gene expression, reduced assembly of F-actin fibers, and loss of focal adhesions. Conclusions: The stellate cell-specific cadherin, PCDH7, is a novel regulator of HSC contractility whose loss leads to cytoskeletal remodeling and sinusoidal relaxation.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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