Stellate cell-specific adhesion molecule protocadherin 7 regulates sinusoidal contraction.

Abstract

Sustained inflammation and hepatocyte injury in chronic liver disease activate hepatic stellate cells (HSCs) to transdifferentiate into fibrogenic, contractile myofibroblasts. We investigated the role of protocadherin 7 (PCDH7), a cadherin family member not previously characterized in liver, whose expression is restricted to HSCs. We created a PCDH7fl/fl mouse line, which was crossed to LRAT-Cre mice to generate HSC-specific PCDH7 knockout animals. HSC contraction in vivo was tested in response to the HSC-selective vasoconstrictor endothelin-1 (ET-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 ET-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 KO cells was impaired Rho-GTPase signaling, as demonstrated by altered gene expression, reduced assembly of F-actin fibers and loss of focal adhesions. The stellate cell-specific cadherin, PCDH7 is a novel regulator of HSC contractility whose loss leads to cytoskeletal remodeling and sinusoidal relaxation.