Multimodal decoding of human liver regeneration.
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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, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a 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 subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. 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. Four-dimensional 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 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. 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 that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.
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Acknowledgements: This work was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z) to N.C.H., a Chan Zuckerberg Initiative Seed Network Grant to N.C.H., and a Tenovus Scotland grant (E20-03) to K.P.M., S. J. Wallace and N.C.H. J.R.P. was supported by a Medical Research Council Precision Medicine PhD studentship. C.A.K. was a cross-disciplinary post-doctoral fellow (XDF) supported by funding from the University of Edinburgh and Medical Research Council (MC_UU_00009/2). T.G.B. was funded by the Wellcome Trust (ref. WT107492Z). S.M. was funded by Cancer Research UK core funding to the CRUK Beatson Institute (refs. A17196 and A31287). J.B.G.M. was supported by a CRUK programme grant (A23390). F.F., J.B.G.M. and L.M.C. were supported by CRUK core funding to the Beatson Institute (A31287) and CRUK core funding to L.M.C. (A23983; DRCRPG-Nov22/100007). D.J.M. was supported by a Medical Research Council Senior Clinical Fellowship (MR/P008887/1). P.R. was supported by a Medical Research Council Clinician Scientist Fellowship (MR/N008340/1) and Medical Research Council Senior Clinical Fellowship (MR/W015919/1). M.M.S. was supported by a Peter Samuel Fellowship. We thank the patients who donated liver tissue for this study; J. Davidson, J. Black, C. Ibbotson and A. Baird of the Scottish Liver Transplant Unit and the research nurses of the Wellcome Trust Clinical Research Facility for assistance with consenting patients for this study; the liver transplant coordinators and surgeons of the Scottish Liver Transplant Unit and the surgeons and staff of the Hepatobiliary Surgical Unit, Royal Infirmary of Edinburgh for assistance in procuring human liver samples; the US ALFSG network for assistance in procuring human liver samples; core facilities and services at the Beatson Institute, in particular the Biological Research Unit & the Beatson Advanced Imaging Resource (BAIR); G. Jacquemet for advice on Cellpose segmentation for IVM analysis; R. Insall and L. Machesky for helpful scientific discussions; W. Mungall for technical support; C. Nicol for help with manuscript illustrations; N. Pham for technical assistance with Incucyte; and C. Winchester and R. Li for critical reading of the manuscript. We acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which has been supported through Birmingham Science City–Experimental Medicine Network of Excellence project. This research was funded in whole, or in part, by the Wellcome Trust (Wellcome Trust Senior Research Fellowship in Clinical Science to N.C.H.; ref. 219542/Z/19/Z). This publication is part of the Human Cell Atlas (www.humancellatlas.org/publications).
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1476-4687
