PhD defence: Intrahepatic cholangiocyte organoids for bile-duct tissue engineering and disease modeling

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The bile ducts form a highly complex network of channels within the liver and deliver bile formed by liver cells to the intestine, which is coordinated by the cholangiocytes (i.e. the epithelial cells that line the biliary tree). Impairment of bile transport could lead to bile duct diseases called cholangiopathies, which are the most common reasons for liver transplantation and present a high economic burden on health care. Therefore, understanding the pathogenesis of cholangiopathies is crucial for the development of new therapeutic strategies for which suitable models are needed. The PhD dissertation “Intrahepatic cholangiocyte organoids for bile-duct tissue engineering and disease modeling” by Zhenguo Wang et al. describes three experimental studies dedicated to this:

  1. The culture of liver organoids in animal-free media. Here, the focus was on finding new extracellular matrices to support liver organoids growth. A scaffold based on hydrogel together with chemically defined medium appeared most suitable for liver organoid differentiation into mature cholangiocytes.
  2. Development of a bile duct on-a-chip. In this study, the liver organoids were used for creating a bioengineered bile duct consisting of mature cholangiocytes cultured on hollow fiber membranes that is compatible with flow. This would facilitate studying bile acids transport and their role in cholangiopathies.
  3. Modeling cholangiopathy in vitro. The liver organoids were used to study drug-induced bile duct injury. The antipsychotic chlorpromazine was found to induce oxidative stress and damage the bile duct cells, which was aggravated in presence of bile acids and an inflammatory mediator.

In conclusion, this thesis developed a step-wise culture system for cholangiocytes, and established a bioengineered bile duct that can recapitulate key structures and functions of cholangiocytes for applications in biliary pathophysiological research and as alternative to animals in drug development studies.

Start date and time
End date and time
Location
Academiegebouw, Domplein 29 & online (livestream link)
PhD candidate
Z. Wang
Dissertation
Intrahepatic cholangiocyte organoids for bile-duct tissue engineering and disease modeling
PhD supervisor(s)
prof. dr. R. Masereeuw
Co-supervisor(s)
dr. B. Spee
More information
Full text via Utrecht University Repository