LAUSR

Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor. Description Hepatic stellate cell–derived neurotrophin-3 is critical for homeostatic proliferation of hepatocytes. Editor’s summary When activated by liver injury, hepatic stellate cells promote repair and regeneration but also drive fibrogenesis and cancer. Trinh et al. explored the role of quiescent hepatic stellate cells in the uninjured liver (see also the Focus by Schönberger and Tchorz). Hepatic stellate cell ablation in adult mice using engineered T cells caused the liver to shrink over time because the hepatocytes stopped proliferating, leading to gradual tissue loss as hepatocytes reached the end of their normal life span and were not replaced. Hepatic stellate cells were a source of neurotrophin-3 (NTF-3), which drove hepatocyte proliferation in vitro and in hepatic stellate cell–depleted mice by stimulating the receptor TRKB. These findings demonstrate that hepatic stellate cells are important for liver homeostasis and that NTF-3 is a hepatocyte mitogen. —Annalisa M. VanHook