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WNT signaling contributes to the extrahepatic bile duct proliferative response to obstruction in mice [24hr. Bulk]

ABSTRACT: Biliary obstruction and cholangiocyte hyperproliferation are important features of cholangiopathies affecting the large extrahepatic bile ducts (EHBD). The mechanisms underlying obstruction-induced cholangiocyte proliferation in the EHBD remain poorly understood. Developmental pathways, such as WNT signaling, have been implicated in regulating injury responses in many tissues, including the liver and bile ducts. To investigate the contribution of WNT signaling to the EHBD cholangiocyte proliferative response to obstructive injury, we conducted a comprehensive study using complementary in vivo and in vitro models with pharmacologic interventions and computational approaches. To model obstruction, we used bile duct ligation (BDL) in mice. Human and mouse biliary organoids and mouse biliary explants were used to investigate the effects of WNT activation and inhibition in vitro. We observed a rapid upregulation of WNT ligand expression associated with increased biliary proliferation following obstruction. Cholangiocytes were identified as both WNT ligand-expressing cells and WNT responsive cells. Inhibition of WNT signaling decreased cholangiocyte proliferation in vivo and in vitro, while activation increased proliferation. WNT proliferative effects on cholangiocytes were β-catenin-dependent. Our studies suggest that cholangiocyte-derived WNT ligands can activate canonical WNT signaling to induce proliferation after obstructive injury. These findings implicate the WNT pathway in injury-induced cholangiocyte proliferation within the EHBD.

ORGANISM(S): Mus musculus

PROVIDER: GSE280724 | GEO | 2025/02/12

REPOSITORIES: GEO

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WNT signaling contributes to the extrahepatic bile duct proliferative response to obstruction in mice

Project description:Biliary obstruction and cholangiocyte hyperproliferation are important features of cholangiopathies affecting the large extrahepatic bile ducts (EHBD). The mechanisms underlying obstruction-induced cholangiocyte proliferation in the EHBD remain poorly understood. Developmental pathways, such as WNT signaling, have been implicated in regulating injury responses in many tissues, including the liver and bile ducts. To investigate the contribution of WNT signaling to the EHBD cholangiocyte proliferative response to obstructive injury, we conducted a comprehensive study using complementary in vivo and in vitro models with pharmacologic interventions and computational approaches. To model obstruction, we used bile duct ligation (BDL) in mice. Human and mouse biliary organoids and mouse biliary explants were used to investigate the effects of WNT activation and inhibition in vitro. We observed a rapid upregulation of WNT ligand expression associated with increased biliary proliferation following obstruction. Cholangiocytes were identified as both WNT ligand-expressing cells and WNT responsive cells. Inhibition of WNT signaling decreased cholangiocyte proliferation in vivo and in vitro, while activation increased proliferation. WNT proliferative effects on cholangiocytes were β-catenin-dependent. Our studies suggest that cholangiocyte-derived WNT ligands can activate canonical WNT signaling to induce proliferation after obstructive injury. These findings implicate the WNT pathway in injury-induced cholangiocyte proliferation within the EHBD.

2025-02-12 | GSE280691 | GEO

WNT signaling contributes to the extrahepatic bile duct proliferative response to obstruction in mice [scRNA-seq]

Project description:Biliary obstruction and cholangiocyte hyperproliferation are important features of cholangiopathies affecting the large extrahepatic bile duct (EHBD). The mechanisms underlying obstruction-induced cholangiocyte proliferation in the EHBD remain poorly understood. Developmental pathways, such as WNT signaling, have been implicated in regulating injury responses in many tissues, including the liver and bile ducts. To investigate the contribution of WNT signaling to the EHBD cholangiocyte proliferative response to obstructive injury, we conducted a comprehensive study using complementary in vivo and in vitro models with pharmacologic interventions and computational approaches. To model obstruction, we used bile duct ligation (BDL) in mice. Human and mouse biliary organoids and mouse biliary explants were used to investigate the effects of WNT activation and inhibition in vitro. We observed a rapid upregulation of WNT ligand expression associated with increased biliary proliferation following obstruction. Cholangiocytes were identified as both WNT ligand-expressing cells and WNT responsive cells. Inhibition of WNT signaling decreased cholangiocyte proliferation in vivo and in vitro, while activation increased proliferation. WNT proliferative effects on cholangiocytes were β-catenin-dependent. Our studies suggest that cholangiocyte-derived WNT ligands can activate canonical WNT signaling to induce proliferation after obstructive injury. These findings implicate the WNT pathway in injury-induced cholangiocyte proliferation within the EHBD.

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2022-05-04 | GSE179599 | GEO

Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases. scRNA-Seq

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2021-01-01 | E-MTAB-9807 | biostudies-arrayexpress

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2022-05-09 | PXD028532 | Pride

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2021-05-31 | GSE163062 | GEO

Prominin-1-expressing Hepatic Progenitor Cells Induce Fibrogenesis in Murine Cholestatic Liver Injury

Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.

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