TY - JOUR
T1 - Evolving Up-regulation of Biliary Fibrosis–Related Extracellular Matrix Molecules After Successful Portoenterostomy
AU - Kyrönlahti, Antti
AU - Godbole, Nimish
AU - Akinrinade, Oyediran
AU - Soini, Tea
AU - Nyholm, Iiris
AU - Andersson, Noora
AU - Hukkinen, Maria
AU - Lohi, Jouko
AU - Wilson, David B.
AU - Pihlajoki, Marjut
AU - Pakarinen, Mikko P.
AU - Heikinheimo, Markku
N1 - Funding Information:
The authors thank the Biomedicum Functional Genomics Unit for helping with the RNA sequencing.
Publisher Copyright:
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85107320941
U2 - 10.1002/hep4.1684
DO - 10.1002/hep4.1684
M3 - Article
C2 - 34141988
AN - SCOPUS:85107320941
SN - 2471-254X
VL - 5
SP - 1036
EP - 1050
JO - Hepatology Communications
JF - Hepatology Communications
IS - 6
ER -