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. (Hepatology Communications 2021;0:1-15).

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia

“…The association between SCTR and liver fibrosis was further strengthened by close correlations of SCTR with TGF-β and PDGF , growth factors known to mediate liver fibrosis 31 , 32 . However, unlike in previous experimental studies, SCTR associated with TGFB2 rather than TGFB1 , which is less abundantly expressed TGF-β isoform in BA 17 , 33 , 34 . Additional studies in cholestatic experimental animal models are needed to clarify whether the secretin/SCTR axis could be targeted to reduce fibrosis and biliary damage in BA 20 , 22 , 25 .…”

“…Herein, we have examined the prognostic and pathophysiological significance of 22 predetermined differentially expressed BA specific candidate genes 17 . Among them, SCTR showed unique associations with PE outcomes and liver injury.…”

“…Using mRNA sequencing, we have recently characterized an extracellular matrix (ECM) molecular fingerprint in BA, a set of 22 genes mechanistically connected to DR and biliary fibrosis 17 . These 22 genes, differentially overexpressed at the time of PE, sustained their highly increased BA specific expression one year after SPE, suggesting their mechanistic importance in driving BA liver injury.…”

Biliary Atresia – emerging diagnostic and therapy opportunities

“…Extracellular matrix (ECM) is critical for providing a niche for several cell types, such as intestinal stem cells [91] , and there is an increasing interest in exploring the role of ECM also for cholangiocytes in BA, as progressive fibrosis is frequently observed in BA patients. Pathway enrichment analysis of BA patients with low survival after KPE revealed that the top 10 most dysregulated pathways were ECM-related [92] and Kyrönlahti et al., (2021) observed an increase in ECM gene expression after KPE [93] . Furthermore, elevated expression of matrix metalloproteinase 7 (MMP7), which modulates ECM by breaking down for example fibronectin and proteoglycans, is seen in extrahepatic cholangiocytes in BA patients and serves as a biomarker for the disease (see below) [ 94 , 95 ].…”

San-Huang-Chai-Zhu Formula Ameliorates Liver Injury in Intrahepatic Cholestasis through Suppressing SIRT1/PGC-1α-Regulated Mitochondrial Oxidative Stress

“…IC is mostly found in pregnant women, accounting for 0.2-2% of all complications in pregnancies [3]. Long-term IC will progress to liver brosis and even cirrhosis, leading to a series of liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and biliary atresia [4,5]. At present, some drugs, such as rosiglitazone, obeticholic acid, and ursodeoxycholic acid (UDCA), are commonly used for IC treatment.…”