An integrative approach to understanding the mechanobiology of liver regeneration

SupervisorsMiguel O. Bernabeu, Neil Henderson

Project description:

The liver has a unique ability to regenerate [1], however in many cases of chronic liver disease this regenerative capacity is overwhelmed. Currently the only effective treatment is liver transplantation; nevertheless demand for donor organs greatly outstrips supply. Hepatocytes comprise ~80% of the liver mass and are the primary functional cells of the liver. It has been well described that during liver regeneration hepatocytes proliferate to restore functional liver mass, however the molecular regulation of this process is poorly understood. In particular, how  neovascularisation and changes in hepatic blood flow dynamics regulate this process is largely unknown. Using a combination of cutting edge intravital imaging techniques and computational modelling we aim to understand in greater depth how the liver regenerates. This will in turn pave the way for the development of new, targeted therapies to augment regeneration of the patient’s own liver.

With the development of intravital imaging and improvements in transgenic mouse technology it is now possible to study biological processes in real time. Building on a published method [2], the laboratory of Prof. Neil Henderson has recently established an abdominal imaging window technique in mice allowing for the long-term imaging of the liver in homeostasis and regeneration. In combination with mouse lines expressing fluorescent endothelial, erythrocyte, and hepatocyte cell cycle reporters, this allows for the targeted imaging of the regenerative niche in the liver.

The group of Dr Miguel O. Bernabeu has pioneered the development of computational models of blood flow for the study of developmental vascular remodelling processes. In close collaboration with vascular biology colleagues, they have contributed to establishing that cell polarisation and migration in response to blood wall shear stress is the main driver behind developmental vascular remodelling [3] and identified the role of Wnt signalling in specifying endothelial cell sensitivity to wall shear stress.

In this project, we will leverage intravital microscopy, image processing, and computational modelling to investigate blood flow dynamics and neovascularisation in the regenerating liver, at both the organ level and cellular level, i.e. in the regenerative niche, and how these processes regulate hepatocyte proliferation and liver regeneration. This combination of intravital imaging and computational approaches provides a unique opportunity to investigate the dynamics of liver homeostasis and regeneration.

This is a unique opportunity for a student with a background in Mathematics, Physics or Engineering to develop new quantitative approaches to study liver regeneration. The student will receive cutting-edge training in intravital microscopy, image processing, and image-based computational modelling of blood flow. The student will benefit from interactions with a large national and international network of researchers applying experimental and theoretical approaches for the characterisation of microvascular biomechanics and mechanobiology, both in development and in disease.

References:

[1] Miyaoka Y, Miyajima A. To divide or not to divide: revisiting liver regeneration. Cell Division. 2013;8:8. doi:10.1186/1747-1028-8-8.

[2] Ritsma L, Steller EJ, Ellenbroek SI, Kranenburg O, Borel Rinkes IH, van Rheenen J. Surgical implantation of an abdominal imaging window for intravital microscopy. Nat Protoc. 2013 Mar;8(3):583-94. doi:10.1038/nprot.2013.026.

[3] Franco CA, Jones ML, Bernabeu MO, Geudens I, Mathivet T, et al. Dynamic Endothelial Cell Rearrangements Drive Developmental Vessel Regression. PLOS Biology. 2015 13(4):e1002125. doi:10.1371/journal.pbio.1002125

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