Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multi-compartment biliary organoids

Hiroaki Ayabe, Erica A. K. DePasquale, Surya P. Amarachintha, Reena Mourya, Wenqi Li, Shreya Nalluri, Sejal R. Fox, Kenichiro Konishi, Pranavkumar Shivakumar () and Jorge A. Bezerra ()
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Hiroaki Ayabe: University of Texas Southwestern Medical Center and Children’s Medical Center
Erica A. K. DePasquale: Cincinnati Children’s Hospital Medical Center
Surya P. Amarachintha: Georgia Southwestern State University
Reena Mourya: University of Texas Southwestern Medical Center and Children’s Medical Center
Wenqi Li: University of Texas Southwestern Medical Center and Children’s Medical Center
Shreya Nalluri: Boston University Center for Computing and Data Sciences
Sejal R. Fox: Cincinnati Children’s Hospital Medical Center
Kenichiro Konishi: Cincinnati Children’s Hospital Medical Center
Pranavkumar Shivakumar: University of Texas Southwestern Medical Center and Children’s Medical Center
Jorge A. Bezerra: University of Texas Southwestern Medical Center and Children’s Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61442-5

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