The long-term goal of our research is to identify pro-regenerative to improve liver regeneration. The only curative therapy for end-stage liver disease is liver transplantation as no regenerative therapies exist. Liver transplantation is limited by donor graft supply. Living donor transplantation or split liver transplantation, in which one organ is split among two patients, rely on the regenerative capacity of the liver to restore its mass. The number of these interventions has increased to gap the bridge between demand and supply but post- hepatectomy or ‘small-for-size’ syndrome, which reflect a regenerative failure, present severe complications for which only supportive but no regenerative therapies exist. We have identified a novel hepatic growth factor, neurotrophin-3 (NTF3), that induces hepatocyte proliferation in culture and increases liver mass after administration to rodents. NTF3 is a member of the nerve growth factor family, that is secreted by hepatic stellate cells (HSC) and signals through tropomyosin kinase receptors (TRKs). While HSCs contribute to liver fibrogenesis during injury, HSCs are known to release growth factors which may be critical during liver regeneration. Using a novel HSC-depletion mouse model that used genetically engineered T cells to deplete HSCs after adoptive transfer, we discovered that HSCs maintain liver zonation, hepatocyte proliferation and liver mass. As liver regeneration occurs staggered in a zonal fashion to ensure functioning hepatocytes at any time during the process, liver zonation is critically important for liver regeneration. Our preliminary data indicate that HSCs and NTF3 promote liver regeneration and that NTF3-TRK signaling is relevant to humans as well. As there are known TRK-agonists and FDA-approved TRK-antagonists, our central hypothesis is that HSCs and HSC- derived NTF3 promote liver regeneration and that TRK-agonists improve liver regeneration. We will test our hypothesis in three specific aims: 1. To determine if NTF3 and TRK signaling maintain liver zonation and promote liver regeneration in rodent models of liver regeneration; 2. To establish NTF3 and TRK signaling in human liver, primary hepatocytes and hepatic organoids; 3. To clarify NTF3-TRK downstream signaling pathways in cultured liver cells. Our proposed studies will provide important insights into a novel hepatocyte growth signaling pathway and generate preclinical data to assess TRK-agonists for potential regenerative therapies.