MassIVE MSV000091082

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GNPS - Absent expansion of Axin2 hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in regeneration

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Description

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. Here we aimed to reconcile these conflicting reports by repeating a key lineage tracing study from pericentral hepatocytes and characterised 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 comparison including transcriptomics, metabolomics and analysis of protein through immunohistochemistry of Axin2CreERT2 mice to WT counterparts. Results: We find that after careful definition of a baseline population there is 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 find substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/b-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. [doi:10.25345/C5MW28Q5Z] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: metabolomics ; Axin2CreERT2 ; hepatocytes

Contact

Principal Investigators:
(in alphabetical order) 		David Sumpton, BICR, United Kingdom
Thomas Bird, BICR, United Kingdom
Submitting User: dsumpton

Publications

May S, Müller M, Livingstone CR, Skalka GL, Walsh PJ, Nixon C, Hedley A, Shaw R, Clark W, Vande Voorde J, Officer-Jones L, Ballantyne F, Powley IR, Drake TM, Kiourtis C, Keith A, Rocha AS, Tardito S, Sumpton D, Le Quesne J, Bushell M, Sansom OJ, Bird TG.
Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration.
J Hepatol. 2023 May;78(5):1028-1036. Epub 2023 Jan 23.

Stephanie May, Miryam Müller, Callum R Livingstone, George L Skalka, Peter J Walsh, Colin Nixon, Ann Hedley, Robin Shaw, William Clark, Johan Vande Voorde, Leah Officer-Jones, Fiona Ballantyne, Ian R Powley, Thomas M Drake, Christos Kiourtis, Andrew Keith, Ana Sofia Rocha, Saverio Tardito, David Sumpton, John Le Quesne, Martin Bushell, Owen J Sansom, Thomas G Bird.
Absent expansion of Axin2 hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in regeneration.
In preparation.

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