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Compensatory growth mechanisms regulated by BMP and FGF signaling mediate liver regeneration in zebrafish after partial hepatectomy

Natalia G. Kan^*,1,2, Dirk Junghans^*,,1,3 and Juan Carlos Izpisua Belmonte^*,,4

^* Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA; and

Center of Regenerative Medicine in Barcelona, Barcelona, Spain

⁴ Correspondence: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA. E-mail: belmonte{at}salk.edu

Here, we describe the zebrafish (Danio rerio) as a vertebrate model system to study liver regeneration with the added benefit of its powerful genetics and screening possibilities to uncover the molecular pathways underlying liver regeneration. We developed a partial hepatectomy (PH) protocol in zebrafish and investigated in detail the cellular and morphological changes during the process of liver regeneration. We show that the type of regenerative response is dependent on the size of the injury sustained by the zebrafish liver. Furthermore, we demonstrate for the first time that the mechanisms of liver regeneration in zebrafish after PH are strikingly similar to those of rodents and humans, with 100% recovery of the liver mass after 6–7 d postsurgery. This occurs via compensatory growth mediated by proliferation of hepatocytes throughout the entire liver remnant. By analyzing transgenic fish expressing dominant-negative forms of either bone morphogenetic protein (BMP) receptor or fibroblast growth factor (FGF) receptor 1, we demonstrate that the BMP and FGF signaling pathways are crucial regulators of the early events during liver regeneration after PH. Our study demonstrates that the mechanisms of liver regeneration in zebrafish are highly similar to the processes ongoing during mammalian liver regeneration and make the adult zebrafish a suitable model system to study the mechanisms of liver regeneration.—Kan, N. G., Junghans, D., Belmonte, J. C. I. Compensatory growth mechanisms regulated by BMP and FGF signaling mediate liver regeneration in zebrafish after partial hepatectomy.

Key Words: hepatocyte proliferation • liver-to-body weight ratio • liver mass restoration • Danio rerio