Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration

May, S. et al. (2023) Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration. Journal of Hepatology, 78(5), pp. 1028-1036. (doi: 10.1016/j.jhep.2023.01.009) (PMID:36702176)

Abstract

Background & Aims: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. Methods: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. Results: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance. Conclusions: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. Impact and implications: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally.

• Item Type: Articles
• Additional Information: The authors would like to thank CRUK Beatson Institute’s histological services, biological services, molecular technology and bioinformatics services, central services, Beatson Advanced Imaging Resource (BAIR) (core funded by CRUK – A17196 and A31287) and the Clinical Pathology Lab (University of Glasgow) for their assistance.
• Keywords: Preclinical model, liver regeneration, Wnt signalling, lineage tracing.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin and May, Dr Steph and Tardito, Dr Saverio and Walsh, Peter and Clark, Mr William and Le Quesne, Professor John and Drake, Dr Tom and Kiourtis, Christos and Muller, Dr Miryam and Sumpton, Mr David and Bird, Dr Thomas and Keith, Mr Andrew and Sansom, Professor Owen and Bushell, Professor Martin and Skalka, Dr George
• Authors: May, S., Muller, M., Livingstone, C. R., Skalka, G. L., Walsh, P. J., Nixon, C., Hedley, A., Shaw, R., Clark, W., Voorde, J. V., Officer-Jones, L., Ballantyne, F., Powley, I. R., Drake, T. M., Kiourtis, C., Keith, A., Rocha, A. S., Tardito, S., Sumpton, D., Le Quesne, J., Bushell, M., Sansom, O. J., and Bird, T. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Hepatology
• Publisher: Elsevier
• ISSN: 0168-8278
• ISSN (Online): 1600-0641
• Published Online: 23 January 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Journal of Hepatology 78(5): 1028-1036
• Publisher Policy: Reproduced under a Creative Commons License