Neuro-biliary talk · Innervation-driven mechanisms of bile duct development
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2023-09-01 → 2025-12-31
- EU contribution
- €206,888
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Innervation-driven mechanisms of bile duct development
The liver is a complex organ made up of several tightly interconnected systems, including the blood vessels and the bile ducts, which collect and transport bile to support digestion. Another important but often overlooked component in the liver is the network of nerve fibers. These nerves have been difficult to study because their cell bodies lie outside the liver, and the fibers are very small compared to other cell types. Nevertheless, they play key roles in health and disease, including common conditions such as non-alcoholic fatty liver disease (NAFLD) and diabetes. Recent observations suggest that liver nerves may also be essential during liver development. In particular, livers from patients with Alagille syndrome, a rare genetic disorder caused by mutations in Notch signalling, lack normal innervation. Alagille syndrome leads to a reduced number of bile ducts, and the only current treatment is liver transplantation. There is therefore an urgent need to better understand the biological mechanisms underlying the disease and to identify new potential therapeutic targets. In this project, we hypothesized that liver innervation provides a key signal that initiates the formation of bile duct structures. This project thus aimed to map the development of liver nerves and investigate the role of nerves in liver development and bile duct formation, using loss-of-function studies and state-of-the-art microscopy techniques for 3D visualisation in mouse models.
Data: CORDIS, © European Union
Project objective
While liver development is well-studied, the signal initiating tubulogenesis of bile ducts therein remains to be identified. Neurites are present in the liver before bile duct tubulogenesis, and in other organs, innervation can instruct tubulogenesis. However, a role for liver innervation in biliary tubulogenesis has not been shown. Preliminary data from my host lab suggest a strong link between both processes: Defective biliary tubulogenesis caused by Notch mutations in Alagille syndrome (ALGS) is preceeded by a lack of liver innervation. I will test the hypothesis that intrahepatic innervation initiates biliary tubulogenesis. First, I will apply 3D staining and imaging techniques to study the establishment of intrahepatic innervation at multiple timepoints during development, and quantify characteristics of innervation in healthy and ALGS mice in depth using automated image analysis. Secondly, I will investigate if liver innervation is required for tubulogenesis by performing nerve ablation studies and analyzing its effect on biliary cells. Finally, I will establish a method to perform transcriptional profiling of liver innervation. The liver is only innervated by nerve endings from extrinsic neurons, and these neurons have their cell bodies in ganglia outside of the organ where also other neurons reside. It has thus not been possible to isolate these cells from the liver and analyse their expression profiles. Using a viral barcode library to label neurons and their axon endings, I will perform single-cell RNA sequencing on those ganglia, and identify and characterize the cells innervating the liver. Enabling expression profiling of extrinsic nerves will be a game changer in the field of organ innervation, and can be applicable to numerous other fields. This project will provide fundamental insights into the developmental functions of liver innervation and the molecular mechanisms underlying biliary tubulogenesis, providing a basis for future therapeutics.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
- View on CORDIS
- DOI: 10.3030/101063809
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50927b494&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5259661c3&appId=PPGMS
Data: CORDIS, © European Union