James K Carter, Ming-Chao Tsai, Nicholas Venturini, Jiangting Hu, John J Lemasters, Miguel Torres Martin, Daniela Sia, Shuang Wang, Youngmin A Lee, Scott L Friedman
{"title":"星状细胞特异性粘附分子原粘连蛋白7调控窦状收缩。","authors":"James K Carter, Ming-Chao Tsai, Nicholas Venturini, Jiangting Hu, John J Lemasters, Miguel Torres Martin, Daniela Sia, Shuang Wang, Youngmin A Lee, Scott L Friedman","doi":"10.1097/HEP.0000000000000782","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>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.</p><p><strong>Approach and results: </strong>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.</p><p><strong>Conclusions: </strong>The stellate cell-specific cadherin, PCDH7, is a novel regulator of HSC contractility whose loss leads to cytoskeletal remodeling and sinusoidal relaxation.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Stellate cell-specific adhesion molecule protocadherin 7 regulates sinusoidal contraction.\",\"authors\":\"James K Carter, Ming-Chao Tsai, Nicholas Venturini, Jiangting Hu, John J Lemasters, Miguel Torres Martin, Daniela Sia, Shuang Wang, Youngmin A Lee, Scott L Friedman\",\"doi\":\"10.1097/HEP.0000000000000782\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>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.</p><p><strong>Approach and results: </strong>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.</p><p><strong>Conclusions: </strong>The stellate cell-specific cadherin, PCDH7, is a novel regulator of HSC contractility whose loss leads to cytoskeletal remodeling and sinusoidal relaxation.</p>\",\"PeriodicalId\":177,\"journal\":{\"name\":\"Hepatology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.9000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hepatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/HEP.0000000000000782\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/16 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/HEP.0000000000000782","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/16 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
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.
期刊介绍:
HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.