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Updated: May 12, 2026
Generation of Organoids from Mouse Extrahepatic Bile Ducts
Published on: April 23, 2019
Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multi-compartment
Hiroaki Ayabe1, Erica A K DePasquale2, Surya P Amarachintha3
1Department of Pediatrics, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
Insights
Neonatal susceptibility to biliary atresia is linked to impaired bile duct development. Inhibiting TGF-β signaling in engineered biliary organoids improved epithelial development and reduced disease severity in mice.
Area of Science:
- Hepatology and developmental biology
- Pediatric gastroenterology and hepatology
- Cellular and molecular biology
Background:
- Neonatal diseases, including biliary atresia, stem from developmental defects in epithelial structures and cellular maturation.
- Biliary atresia is a severe pediatric cholangiopathy impacting bile duct development.
- Understanding biliary development is crucial for addressing neonatal susceptibility to liver diseases.
Purpose of the Study:
- To investigate human biliary development and its vulnerability to biliary atresia.
- To engineer multi-compartment biliary organoids (MBOs) for studying biliary development.
- To explore the role of TGF-β/Activin-SMAD2/3 signaling in biliary atresia.
Main Methods:
- Co-culture of human liver-derived epithelial organoid cells with endothelial and mesenchymal cells to create MBOs.
- Comparison of MBOs derived from normal and diseased livers to identify developmental defects.
- Inhibition of TGF-β signaling in MBOs and a mouse model of biliary atresia.
Main Results:
- Normal MBOs replicated bile duct epithelium and peribiliary glands (PBGs).
- Diseased MBOs showed defective epithelial layers, epithelial-mesenchymal transition (EMT), and activated TGF-β/Activin-SMAD2/3 signaling.
- TGF-β inhibition suppressed EMT, promoted biliary epithelial development in MBOs, and ameliorated experimental biliary atresia in mice.
Conclusions:
- TGF-β-dependent EMT is a key regulator of bile duct epithelial development.
- Modulating TGF-β signaling can influence neonatal susceptibility to biliary injuries.
- Engineered MBOs provide a valuable model for studying biliary development and disease.
Abstract:
Deficiencies in the development of epithelial structures and delays in cellular maturation can increase the susceptibility of neonates to disease early in life. To investigate human biliary development and its vulnerability to biliary atresia, a severe pediatric cholangiopathy, we engineered multi-compartment biliary organoids (MBOs) from co-cultures of human liver-derived epithelial organoid cells with human endothelial and mesenchymal cells. MBOs derived from normal livers effectively replicated the epithelial structure of the bile duct epithelium and peribiliary glands (PBGs). Conversely, MBOs from diseased livers exhibited defective epithelial layers, a significant epithelial-mesenchymal transition (EMT), and an activation of the TGF-β/Activin-SMAD2/3 signaling, primarily due to intermediary cell sub-populations. Inhibition of TGF-β signaling suppressed EMT and promoted biliary epithelial development in human MBOs and suppressed the phenotype of experimental biliary atresia in neonatal mice. Thus, the modulation of TGF-β-dependent EMT regulates bile duct epithelial development and influences the susceptibility of neonates to biliary injuries.
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