Absent expansion of pericentral hepatocytes and altered physiology in Axin2CreERT2 mice

Abstract

Abstract/IntroductionUnderstanding how the liver regenerates is a key biological question. Hepatocytes are the principle regenerative population in the liver. Recently, numerous lineage tracing studies (which apply genetic tagging to a restricted population and track its descendants over time) have reported conflicting results using a variety of hepatocyte based reporting systems in mice1,2. The first significant lineage tracing from a distinct subpopulation of hepatocytes in homeostasis reported hyper-proliferation of self-renewing pericentral hepatocytes with their subsequent expansion across the liver lobule3. This study used a CreERT2 construct knocked into the endogenous Axin2 locus; here termed Axin2CreERT2. Subsequent studies, using either a different pericentral marker (Lgr54) or a different AxinCreERT2 transgene5, did not show lineage tracing. Here we aim to reconcile these discrepancies by re-evaluating lineage tracing in the Axin2CreERT2 knock-in model and explore the physiological consequences of this mutant allele. We were unable to find evidence of expansion of an Axin2CreERT2 labelled population and show that this population, whilst zonated, is spread throughout the lobule rather than being zonally restricted. Finally, we report that this allele results in profound perturbation of the Wnt pathway and physiology in the mouse.

The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease

“…Neither 5-ethynyl-2'-deoxyuridine (EdU) labeling analyses nor LGR5-, AXIN2-, bacterial artificial chromosome (BAC)-LGR5-, BAC-AXIN2-, or adeno-associated virus (AAV)-based lineage tracing experiments observed increased proliferative potential of pericentral hepatocytes and/or cellular streaming into zone 1. [12,[32][33][34][35] Instead, recent studies using combinations of different tracing models, [36] recording of proliferation events over time, [37] spatial transcriptomics profiling, [23] or AAV-based labeling [33] suggest that hepatocytes in zone 2 have increased proliferative potential during homeostasis over hepatocytes in other liver zones.…”