Evolving Up-regulation of Biliary Fibrosis-Related Extracellular Matrix Molecules After Successful Portoenterostomy

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Kyronlahti , A , Godbole , N , Akinrinade , O , Soini , T , Nyholm , I , Andersson , N , Hukkinen , M , Lohi , J , Wilson , D B , Pihlajoki , M , Pakarinen , M P & Heikinheimo , M 2021 , ' Evolving Up-regulation of Biliary Fibrosis-Related Extracellular Matrix Molecules After Successful Portoenterostomy ' , Hepatology communications , vol. 5 , no. 6 , pp. 1036-1050 . https://doi.org/10.1002/hep4.1684

Title: Evolving Up-regulation of Biliary Fibrosis-Related Extracellular Matrix Molecules After Successful Portoenterostomy
Author: Kyronlahti, Antti; Godbole, Nimish; Akinrinade, Oyediran; Soini, Tea; Nyholm, Iiris; Andersson, Noora; Hukkinen, Maria; Lohi, Jouko; Wilson, David B.; Pihlajoki, Marjut; Pakarinen, Mikko P.; Heikinheimo, Markku
Contributor organization: HUS Children and Adolescents
Developmental and tumor biology research group
Children's Hospital
Clinicum
University of Helsinki
Helsinki University Hospital Area
Lastenkirurgian yksikkö
HUSLAB
University Management
Department of Pathology
Medicum
Helsinki One Health (HOH)
Date: 2021-06
Language: eng
Number of pages: 15
Belongs to series: Hepatology communications
ISSN: 2471-254X
DOI: https://doi.org/10.1002/hep4.1684
URI: http://hdl.handle.net/10138/340174
Abstract: Successful portoenterostomy (SPE) improves the short-term outcome of patients with biliary atresia (BA) by relieving cholestasis and extending survival with native liver. Despite SPE, hepatic fibrosis progresses in most patients, leading to cirrhosis and a deterioration of liver function. The goal of this study was to characterize the effects of SPE on the BA liver transcriptome. We used messenger RNA sequencing to analyze global gene-expression patterns in liver biopsies obtained at the time of portoenterostomy (n = 13) and 1 year after SPE (n = 8). Biopsies from pediatric (n = 2) and adult (n = 2) organ donors and other neonatal cholestatic conditions (n = 5) served as controls. SPE was accompanied by attenuation of inflammation and concomitant up-regulation of key extracellular matrix (ECM) genes. Highly overexpressed genes promoting biliary fibrosis and bile duct integrity, such as integrin subunit beta 6 and previously unreported laminin subunit alpha 3, emerged as candidates to control liver fibrosis after SPE. At a cellular level, the relative abundance of activated hepatic stellate cells and liver macrophages decreased following SPE, whereas portal fibroblasts (PFs) and cholangiocytes persisted. Conclusion: The attenuation of inflammation following SPE coincides with emergence of an ECM molecular fingerprint, a set of profibrotic molecules mechanistically connected to biliary fibrosis. The persistence of activated PFs and cholangiocytes after SPE suggests a central role for these cell types in the progression of biliary fibrosis.
Subject: 3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion


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