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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Associate Professor Pau Sancho Bru, University of Barcelona,
- Second opponent: Professor Mathieu Hautefeuille, Sorbonne Université, Paris
- Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo
Chair of the Defence
Professor Bjørn Steen Skålhegg, University of Oslo
Principal Supervisor
Professor Stefan Krauss, University of Oslo
Summary
Liver disease models are essential for studying hepatic pathology, which poses a significant worldwide health burden. Hepatic stellate cells (HSCs) activate during chronic liver disease and play a crucial role in driving fibrotic scarring, ultimately leading to liver failure.
Obtaining and cultivating human primary HSCs for in vitro liver disease modeling is challenging. Generating HSCs from human pluripotent stem cells (hPSCs) has been proposed as a solution, providing an unlimited cell source relevant to human hepatic physiology and pathology. However, the applicability of such stem cell-derived HSCs (scHSCs) for liver disease modeling has not been extensively characterized.
The primary goal of this thesis was to establish and evaluate an scHSC system for in vitro liver disease modeling. scHSCs were generated from multiple hPSC lines to investigate the advantages and challenges of the system, focusing on disease modeling and comparison to human primary HSCs.
The scHSCs proved comparable and complementary to existing HSC models, especially within the first five days after differentiation. The scHSC model was particularly useful for studying intracellular vitamin A and lipid droplets, essential aspects of HSCs in the healthy liver. We found that both compounds were retained during disease modeling by pro-fibrotic TGF-β stimulation, while simultaneously demonstrating a synergistic relationship between the loss of said compounds and the severity of HSC activation, providing valuable insights in an area with conflicting data.
Additionally, we observed a reduction in glycolysis in scHSCs under diseased conditions, contributing necessary data on the understudied topic of HSC energy metabolism. Finally, we demonstrated the scHSCs as effector cells in studying liver disease-associated biomarkers.
In conclusion, we comprehensively demonstrated that the presented scHSC model is a valuable asset in the rapidly progressing field of in vitro liver disease modeling.
Additional information
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