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

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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 the 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 capturing regenerative cell behaviours, which is crucial 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 sufficient to trigger local liver progenitor-like cell (LPC)- mediated regeneration, challenging the current understanding of liver regeneration. Surprisingly, the LPC response is also elicited in adjacent uninjured tissue, at up to 100 μm distance to the injury. Moreover, dynamic biliary network rearrangement suggests active cell movements from uninjured tissue in response to substantial hepatocyte loss as an integral step of LPC-mediated liver regeneration. This precisely targetable liver cell ablation tool will enable the discovery of key molecular and morphogenetic regeneration paradigms.

OriginalsprogEngelsk
TidsskriftDevelopment (Cambridge)
Vol/bind151
Udgave nummer4
Sider (fra-til)1-18
ISSN0950-1991
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by Novo Nordisk Foundation grants (NNF19OC0058327 to E.A.O., NNF17CC0026756 to E.M.A.), the National Institute of Genetics (NIG-JOINT 13A2018 to E.A.O.), Novo Nordisk Fonden (NNF17OC0031204 to P.R.L.), a Danmarks Grundforskningsfond grant (DNRF116 to E.A.O.), a Peter and Emma Thomsens Legat award (1051 to J.B.C.) and the John and Birthe Meyer Foundation (P.R.L.). This work received funding from the European Union’s Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie grant agreement 798510 to C.S.L.B.).

Funding Information:
and continued advice with image acquisition, analysis and quantification, and the department of experimental medicine for expert fish care. We are grateful to Drs A. Boni and P. Strnad (Viventis) for light-sheet microscopy. The Novo Nordisk Foundation Center for Stem Cell Biology was supported by a Novo Nordisk Foundation grant number NNF17CC0027852.

Publisher Copyright:
© 2024 Company of Biologists Ltd. All rights reserved.

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