ERA-NET: Dynamic bile flow modelling and cellular sensing in primary sclerosing cholangitis

After some lead-in delays, the project has worked according to protocol and the Oslo contribution - which has had an emphasis on patient materials and advanced biobanking - has had its deliverables according to the original project description. The international partners, mainly technical engineers and molecular biologists, received regular transfers of processed material which has been analyzed according to the project description. In Oslo, key emphasis has been to support development and deliverables along two project axes: The first project track was related to WP5, and aimed to establish and test mathematical models for fluid dynamics in three-dimensional reconstructions of special X-ray images (so called magnetic resonance imaging, MRI). We established regular follow-up (annual) of relevant patients both in Oslo and Bergen to ensure that sufficient data was available for this project axis. The mathematical models were developed by the Israel Institute of Technology, project partner, on the basis of anonymized images from Norwegian patients. Results of the mathematical modeling can be aligned with clinical disease behavior and thereby pave the way for personalized dosage of a medication believed to have efficacy in PSC (ursodeoxycholic acid). The reason why this modeling may prove crucial, is that the mechanism of action of the drug involves enhanced bile flow. In the patients, there are strictures (narrow parts), and under too high doses, pressure injuries may occur. At the same time, sufficient dose must be given to accomplish the benefits of the treatment. The first publications from this axis are published and more are being planned, e.g. Meyer et al., A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule. Cell Syst. 2017: (17)30052-2. The second project axis of high relevance to the Norwegian contribution was related to WP4. This project axis have had its focus on the three-dimensional microstructure of the liver in the diseased patients. In Norway, PSC is the most important indication for liver transplantation (unlike other countries), meaning there is a unique access to surplus biological material from the explanted, sick liver from patients undergoing liver transplantation, a complex undertaking, both in practical/logistical terms as well as for material preparation protocols. This unique material collection was secured thanks to the employees supported by the project, and also includes samples from tissue from patients with other liver diseases (control patients). Two batches of biological material has been transferd to partners at the Max-Planck-Institute of Molecular Cell Biology & Genetics in Germany, who are performing multiple types of sophisticated staining and microscopic imaging of the tissues. These techiniques made it possible to reconstruct three-dimensional images of the smallest bile ducts (canaliculi). These reconstructions on one side provided a map of pressure-related injuries resulting from the obstructed bile flow in PSC, and on the other side also provided a basis for modeling of bile flow at a microscopic level using the same mathematic models as used for the MRI images (see above). Findings are being aligned with and compared with (still ongoing) findings in the animal models (from WP2). The first articles from this axis have been published and more are underway, e.g. Brosch et al., Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat Commun 2018;9:4150.

Prosjektet har gitt helt ny kunnskap om leverens 3-dimensjonale mikroarkitektur, både i normaltilstand og ved sykdom. Dette er relevant for både aktuelle sykdomsgruppe (primær skleroserende cholangitt), men har også gitt innsikt av generell betydning for sykdomsutvikling i leveren. Væskeflytanalysene har gitt ny kunnskap om galleflyt, både i normaltilstand og ved innsnevringer, noe som er relevant for utvikling av persontilpasset medisin for pasienter ved galleveissykdommer som involverer endringer i væskeflyt.

Medical need: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by fibroobliterative destruction of the intra and/or extra-hepatic bile ducts, leading to liver cirrhosis. There is no effective medical therapy for PSC, and the majority of patients will eventually require liver transplantation. Following a primary immunological insult, biliary flow obstruction leads to pressure damage to the biliary epithelium and hepatocytes and drives disease progression. Approach: We will use a systems biology approach to model the hydrodynamic and signalling consequences of the altered biliary flow. We will: i) experimentally map and model the 3D structure and cellular interactions of small bile ducts in well characterized and long-term followed patients and animal models of PSC, ii) perform 3D geometry-based hydrodynamic modelling, iii) calibrate models on intravital imaging of biliary flow in murine models, iv) look at the consequences on cellular programing using in-situ functional genomics and v) mechanistically analyse and model biliary pressure sensing and it´s signalling consequences. Yield: The resulting spatiotemporal model of altered bile flow and signalling will allow A) to identify targets for the utterly needed pharmacological intervention to prevent biliary pressure damage and B) pave the way for personalized pharmacological biliary pressure optimization in affected patients. Expertise & Consortium: Intriguingly, biliary flow dynamics, pressure sensing and the signalling consequences are as yet very poorly understood. Thus, the consortium unites established liver research with mechanosensing and modelling expertise that has never been systematically applied in a PSC context. Specifically, the consortium unites renowned liver research centres from Norway (clinical PSC) and Austria (experimental PSC) with fluid dynamics (Israel), high-definition 3D tissue reconstruction, functional genomics (Germany) and mechanosensing (France).