IGFBP2 expressing midlobular hepatocytes preferentially contribute to liver homeostasis and regeneration

While midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated a Igfbp2-CreER knockin strain, which specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21% to 41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with DDC, IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased substantially with fasting, we used single nuclear transcriptomics to explore zonation as a function of nutrition, revealing that the zonal division of labor shifts dramatically with fasting. These studies demonstrate the contribution of IGFBP2-labeled zone 2 hepatocytes to liver homeostasis and regeneration. HighlightsO_LILineage tracing showed that midlobular hepatocytes proliferate during homeostasis. C_LIO_LIZone 2 cells were protected from portal and centrilobular injuries and replaced lost hepatocytes. C_LIO_LIFasting induced significant changes in liver zonation. C_LI eTOC statementThe liver consists of different zones with spatial heterogeneity in their metabolic functions. Here, a new Igfbp2-CreER line enabled direct tracing of midlobular hepatocytes, which showed that IGFBP2+ cells serve as a source of new hepatocytes during normal homeostasis and regeneration.