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Multimodal decoding of human liver regeneration

View ORCID ProfileKP Matchett, View ORCID ProfileJR Wilson-Kanamori, View ORCID ProfileJR Portman, View ORCID ProfileCA Kapourani, F Fercoq, View ORCID ProfileS May, JBG Mackey, View ORCID ProfileM Brice, E Zajdel, M Beltran, View ORCID ProfileEF Sutherland, GC Wilson, SJ Wallace, L Kitto, View ORCID ProfileNT Younger, View ORCID ProfileR Dobie, View ORCID ProfileGC Oniscu, View ORCID ProfileSJ Wigmore, P Ramachandran, View ORCID ProfileCA Vallejos, View ORCID ProfileNO Carragher, KJ Simpson, View ORCID ProfileTJ Kendall, Acute Liver Failure Study Group, JA Rule, WM Lee, View ORCID ProfileM Hoare, CJ Weston, View ORCID ProfileJC Marioni, View ORCID ProfileST Teichmann, View ORCID ProfileTG Bird, View ORCID ProfileLM Carlin, View ORCID ProfileNC Henderson
doi: https://doi.org/10.1101/2023.02.24.529873
KP Matchett
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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JR Wilson-Kanamori
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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JR Portman
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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CA Kapourani
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
2MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
3School of Informatics, University of Edinburgh, Edinburgh, UK
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F Fercoq
4Cancer Research UK Beatson Institute, Glasgow, UK
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S May
4Cancer Research UK Beatson Institute, Glasgow, UK
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JBG Mackey
4Cancer Research UK Beatson Institute, Glasgow, UK
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M Brice
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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E Zajdel
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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M Beltran
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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EF Sutherland
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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GC Wilson
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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SJ Wallace
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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L Kitto
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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NT Younger
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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R Dobie
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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GC Oniscu
5Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK
6Division of Transplant Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
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SJ Wigmore
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
7University Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK
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P Ramachandran
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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CA Vallejos
2MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
8The Alan Turing Institute, London, UK
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NO Carragher
9Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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KJ Simpson
10Department of Hepatology, University of Edinburgh and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
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TJ Kendall
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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JA Rule
11Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
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WM Lee
11Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
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M Hoare
12Early Cancer Institute, University of Cambridge, Cambridge, UK
13Department of Medicine, University of Cambridge, Cambridge, UK
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CJ Weston
14NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
15Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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JC Marioni
16Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
17European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK
18Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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ST Teichmann
18Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
19European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK
20Department of Physics, Cavendish Laboratory, Cambridge, UK
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TG Bird
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
4Cancer Research UK Beatson Institute, Glasgow, UK
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LM Carlin
4Cancer Research UK Beatson Institute, Glasgow, UK
21School of Cancer Sciences, University of Glasgow, Glasgow, UK
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NC Henderson
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
22MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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  • For correspondence: Neil.Henderson@ed.ac.uk
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Abstract

The liver has a unique ability to regenerate1,2, however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option3-5. To advance our understanding of human liver regeneration and to inform design of pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNA-seq) combined with spatial profiling of healthy and ALF explant human livers to generate the first single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation which emerges during human liver regeneration, and a corollary migratory hepatocyte subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Importantly, interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. 4-D intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 expression reduces HGF-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Taken together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation which mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may open up new areas of therapeutic discovery in regenerative medicine.

Competing Interest Statement

N.C.H. has received research funding from AbbVie, Pfizer, Gilead, Boehringer-Ingelheim and Galecto, and is an advisor or consultant for Astra-Zeneca, Galecto, GSK, MSD, Pliant Therapeutics, Ambys Medicines, Mediar Therapeutics and Q32 Bio.

Footnotes

  • https://figshare.com/articles/media/Multimodal_decoding_of_human_liver_regeneration/22100333

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 25, 2023.
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Multimodal decoding of human liver regeneration
KP Matchett, JR Wilson-Kanamori, JR Portman, CA Kapourani, F Fercoq, S May, JBG Mackey, M Brice, E Zajdel, M Beltran, EF Sutherland, GC Wilson, SJ Wallace, L Kitto, NT Younger, R Dobie, GC Oniscu, SJ Wigmore, P Ramachandran, CA Vallejos, NO Carragher, KJ Simpson, TJ Kendall, Acute Liver Failure Study Group, JA Rule, WM Lee, M Hoare, CJ Weston, JC Marioni, ST Teichmann, TG Bird, LM Carlin, NC Henderson
bioRxiv 2023.02.24.529873; doi: https://doi.org/10.1101/2023.02.24.529873
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Multimodal decoding of human liver regeneration
KP Matchett, JR Wilson-Kanamori, JR Portman, CA Kapourani, F Fercoq, S May, JBG Mackey, M Brice, E Zajdel, M Beltran, EF Sutherland, GC Wilson, SJ Wallace, L Kitto, NT Younger, R Dobie, GC Oniscu, SJ Wigmore, P Ramachandran, CA Vallejos, NO Carragher, KJ Simpson, TJ Kendall, Acute Liver Failure Study Group, JA Rule, WM Lee, M Hoare, CJ Weston, JC Marioni, ST Teichmann, TG Bird, LM Carlin, NC Henderson
bioRxiv 2023.02.24.529873; doi: https://doi.org/10.1101/2023.02.24.529873

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