Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia

Area of Science:

• Neonatal Hepatology
• Gastroenterology
• Developmental Biology

Background:

• Biliary atresia is a severe neonatal cholestatic liver disease with unknown causes.
• It involves inflammation and fibrosis of the bile ducts, leading to liver dysfunction.
• Understanding abnormal cholangiocyte development is crucial for identifying therapeutic targets.

Purpose of the Study:

• To investigate the mechanisms underlying abnormal cholangiocyte development in biliary atresia.
• To generate and characterize biliary organoids from infants with biliary atresia.
• To explore potential therapeutic interventions using growth factors.

Main Methods:

• Biliary organoids were generated from liver biopsies of infants with biliary atresia and controls.
• Organoid morphology, gene expression, and cellular markers were analyzed.
• The effect of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) on organoid development was assessed.

Main Results:

• Biliary atresia organoids exhibited halted epithelial development, with abnormal cell polarity and increased permeability.
• These organoids showed decreased expression of EGF and FGF2 signaling pathway genes.
• Treatment with EGF+FGF2 restored polarity, improved cell junctions, and decreased permeability in biliary atresia organoids.

Conclusions:

• Biliary atresia organoids are a viable model to study epithelial development defects.
• EGF and FGF2 can induce developmental markers, improve cell-cell junctions, and reduce epithelial permeability.
• These findings suggest EGF and FGF2 as potential strategies to promote cholangiocyte maturation and function in biliary atresia.