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


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.

SUBMITTER: Kyronlahti A 

PROVIDER: S-EPMC8183171 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Kyrönlahti Antti A   Godbole Nimish N   Akinrinade Oyediran O   Soini Tea T   Nyholm Iiris I   Andersson Noora N   Hukkinen Maria M   Lohi Jouko J   Wilson David B DB   Pihlajoki Marjut M   Pakarinen Mikko P MP   Heikinheimo Markku M  

Hepatology communications 20210209 6


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  ...[more]

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