The liver has a unique ability to regenerate, however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option
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 present snRNA-seq of 72,262 nuclei from healthy (n=9), acetaminophen-induced acute liver failure (n=10), and nonA-E hepatitis acute liver failure (n=12) human liver tissue.
We present a snRNA-seq time course dataset of 59,051 nuclei and spatial profiling from mouse liver tissue following acetaminophen injury.
We provide an open-access, interactive browser to allow assessment and visualisation of gene expression in multiple hepatic cell lineages in our datasets. Some of the datasets provided have been downsampled in this interactive browser to facilitate efficiency and speed of the application. All full datasets can be found on GEO.
The bioRxiv version of the manuscript can be found at https://www.biorxiv.org/content/10.1101/2023.02.24.529873v1
The liver has a unique ability to regenerate, however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option. 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.