Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver

The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity. In the uninjured liver, a population of self-renewing, diploid hepatocytes is identified near the central vein; these cells respond to Wnt signals that are provided by the adjacent central vein endothelial cells, and can give rise to all other hepatocytes to maintain liver homeostasis. How new hepatocytes arise in the adult liver as part of the routine of homeostasis remains unclear. Roel Nusse and colleagues have addressed this question using sophisticated methods of cell labelling. They identify a population of proliferating hepatocytes located near the central vein that are diploids — in contrast to mature cells that are polypoid — and express a liver progenitor marker. These cells respond to Wnt signals, provided by the adjacent endothelial cells from the central vein, to become polyploid hepatocytes capable of replacing all the hepatocyte types needed to maintain liver homeostasis.