LiverZap: A chemoptogenetic tool for global and locally restricted hepatocyte ablation to study cellular behaviours in liver regeneration

Abstract The liver restores its mass and architecture after injury. Yet, investigating morphogenetic cell behaviours and signals that repair tissue architecture at high spatiotemporal resolution remains challenging. We developed LiverZap, a tuneable chemoptogenetic liver injury model in zebrafish. LiverZap employs formation of a binary FAP-TAP photosensitiser followed by brief near-infrared illumination inducing hepatocyte-specific death and recapitulating mammalian liver injury types. The tool enables local hepatocyte ablation and extended live imaging of regenerative cell behaviours, critical for studying cellular interactions at the interface of healthy and damaged tissue. Applying LiverZap, we show that targeted hepatocyte ablation in a small region-of-interest is unexpectedly sufficient to trigger Liver Progenitor-like Cell (LPC)-mediated regeneration, challenging the current understanding of LPC activation. Associated dynamic bilary network rearrangement and E-cadherin relocalisation suggest modulation of cell adhesion as an integral step of LPC-mediated liver regeneration. This precisely targetable live cell ablation model will enable addressing of key regeneration paradigms.