Lgr5+ pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis

Abstract

Significance Liver has a remarkable regenerative capacity following injuries. However, the cellular dynamics of how hepatocytes are replenished during homeostasis and upon liver injuries remains largely unclear. By using genetic lineage tracing strategies on rare Lgr5+ hepatocytes surrounding the central veins of the liver lobule, this study shows that Lgr5+ hepatocytes are self-maintained during normal homeostasis and various liver injuries, and contributed to hepatocarcinogesis in two different hepatocellular carcinoma (HCC) models. Our findings provide an insight on hepatocyte regeneration under homeostasis and liver injuries and uncover Lgr5+ hepatocytes as potential cellular origin in HCC development. Emerging evidence suggests that hepatocytes are primarily maintained by self-renewal during normal liver homeostasis, as well as in response to a wide variety of hepatic injuries. However, how hepatocytes in distinct anatomic locations within the liver lobule are replenished under homeostasis and injury-induced regeneration remains elusive. Using a newly developed bacterial artificial chromosome (BAC)-transgenic mouse model, we demonstrate that Lgr5 expression in the liver is restricted to a unique subset of hepatocytes most adjacent to the central veins. Genetic lineage tracing revealed that pericentral Lgr5+ hepatocytes have a long lifespan and mainly contribute to their own lineage maintenance during postnatal liver development and homeostasis. Remarkably, these hepatocytes also fuel the regeneration of their own lineage during the massive and rapid regeneration process following two-thirds partial hepatectomy. Moreover, Lgr5+ hepatocytes are found to be the main cellular origin of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) and are highly susceptible to neoplastic transformation triggered by activation of Erbb pathway. Our findings establish an unexpected self-maintaining mode for a defined subset of hepatocytes during liver homeostasis and regeneration, and identify Lgr5+ pericentral hepatocytes as major cells of origin in HCC development.