Model systems of intrahepatic ductopenia, a common finding in patients with Alagille syndrome (ALGS), need to be further studied, researchers report in a new study published in Advanced Science. They studied important methodological details to integrate biliary architecture of liver tissue into in vitro models.

“Here, we emphasize a materials and cellular characterization approach, demonstrating the potential to
investigate additional aspects of cholangiocyte functionality including permeability, shear stress response, and transport of bile fluid components such as cholic/chenodeoxycholic acids or xenobiotics,” the authors said.

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This new pipeline used adult-derived primary human cholangiocytes to build branched epithelial structures that mimicked the native biliary tissue and maintained cholangiocyte-specific function. This was accomplished by using a combination of extracellular matrix with mitogen stimulation in a controlled in vitro microenvironment.

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The biliary network assembly was regulated by the Notch signaling. “While Notch signaling has been thoroughly investigated in its role in directing intrahepatic biliary branching during development, there is limited evidence of translating these findings into a human relevant in vitro system,” the authors recognized.

In addition, the results of this study corroborated the crosstalk between Notch and epidermal growth factor (EGF) signaling pathways in biliary morphogenesis. EGF stimulation during branching morphogenesis was accompanied by an upregulation of the Notch signaling.

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The system developed by Smith et al shows potential to be included in future liver tissue engineering experiments. However, they pointed to some limitations, including the need for further validation of the human cellular model selected to produce the in vitro system.


Smith Q, Bays J, Li L, Shareef H, Chen CS, Bhatia SN. Directing cholangiocyte morphogenesis in natural biomaterial scaffolds. Adv Sci. Published online November 16, 2021. doi:10.1002/advs.202102698