Cited by 7Liver physiology and pathologyLiver Diseases and ImmunityLiver Disease Diagnosis and Treatment

Stellate cell-specific adhesion molecule protocadherin 7 regulates sinusoidal contraction

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Carter, James K., Tsai, Ming-Chao, Venturini, Nicholas, Hu, Jiangting, Lemasters, John J., Torres Martin, Miguel, Sia, Daniela, Wang, Shuang +2 more·2024·Hepatology

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 PCDH7 fl/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 PCDH7 fl/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.

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Authors
Carter, J. K., Tsai, M.-C., Venturini, N., Hu, J., Lemasters, J. J., Torres Martin, M., Sia, D., Wang, S., Lee, Y. A., & Friedman, S. L.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Chang Gung University (TW)
  • Medical University of South Carolina (US)
  • Genetics Department, Clinical Genomics Unit, Clinical Genetics Service, Germans Trias i Pujol University Hospital, Barcelona, Spain
  • Vanderbilt University Medical Center (US)
Corresponding author
Friedman, Scott L.
Venue
Hepatology
Published
2024-02-16
Volume
80
Issue
3
Pages
566-577
ISSN
0270-9139 (ISSN-L)
OpenAlex
W4391924889
Cited by
7
References
45
Citations by year
2026: 2 · 2025: 4 · 2024: 1
FWCI
1.83
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Medical University of South Carolina
  • University of South Carolina
  • National Institutes of Health (1s10od028663-01, 1s10od018113-01a1)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA025379)
  • National Cancer Institute (R01CA285580, U01CA288425, P50CA236733, P30CA138313, P30CA196521)
  • National Institute of General Medical Sciences (T32GM062754, T32GM007280, P20GM103542, P20GM130457)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056621, R01DK119523, R01DK056621, R01DK128289, R01DK136016, P30DK058404, P30DK123704)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
hepatic stellate cells, endothelin-1, cadherins, Rho GTPase signaling, focal adhesions, liver fibrosis, chronic liver disease
MeSH terms
Protocadherins, Animals, Cells, Cultured, Cadherins, Mice, Knockout, Endothelin-1, Mice, Hepatic Stellate Cells

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