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

Author

Listed:
  • 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
    Kitasato University School of Medicine)

  • 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)

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.

Suggested Citation

  • Hiroaki Ayabe & Erica A. K. DePasquale & Surya P. Amarachintha & Reena Mourya & Wenqi Li & Shreya Nalluri & Sejal R. Fox & Kenichiro Konishi & Pranavkumar Shivakumar & Jorge A. Bezerra, 2025. "Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multi-compartment biliary organoids," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61442-5
    DOI: 10.1038/s41467-025-61442-5
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