The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.

肝脏非凡的再生能力是由多种生长因子和细胞因子精心策划的。成纤维细胞生长因子受体 3 (Fgfr3) 在肝细胞癌中经常过度表达并促进癌症侵袭性，而其在肝脏稳态、修复和再生中的作用尚不清楚。我们在这里展示了 Fgfr3 由健康肝脏中的肝细胞表达。其主要配体 Fgf9 主要由非实质细胞表达并在损伤时上调。肝细胞中缺乏 Fgfr3 的小鼠在急性毒素治疗后表现出增加的组织坏死和长期损伤后更多的过度纤维化。正如综合流式细胞术分析所揭示的，这不是非受伤肝脏免疫学改变的结果。相当，Fgfr3 的缺失改变了肝细胞中代谢和促纤维化基因的表达。这些结果确定了旁分泌 Fgf9-Fgfr3 信号通路，该通路可防止毒素诱导的细胞死亡和由此产生的肝纤维化，并表明 FGFR3 配体可用于治疗目的。