IGFBP2 expressing midlobular hepatocytes preferentially contribute to liver homeostasis and regeneration

Abstract 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. Highlights Lineage tracing showed that midlobular hepatocytes proliferate during homeostasis. Zone 2 cells were protected from portal and centrilobular injuries and replaced lost hepatocytes. Fasting induced significant changes in liver zonation. eTOC statement The 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.