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.
Subject(s)
Liver Failure, Acute , Liver Regeneration , Animals , Female , Humans , Male , Mice , Acetaminophen/pharmacology , Cell Lineage , Cell Movement/drug effects , Cell Proliferation/drug effects , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Hepatocyte Growth Factor/metabolism , Hepatocyte Growth Factor/pharmacology , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Liver/cytology , Liver/drug effects , Liver/pathology , Liver Failure, Acute/pathology , Liver Failure, Acute/chemically induced , Liver Regeneration/drug effects , Mice, Inbred C57BL , Necrosis/chemically induced , Regenerative Medicine , Single-Cell Gene Expression Analysis , Wound HealingABSTRACT
Back pain is a common symptom among patients presenting to the acute medical unit. We describe the case of a 55-year-old man with a brief history of fatigue and severe back pain, unresponsive to escalating doses of opiate analgesia. Blood tests and imaging studies were unremarkable and a functional diagnosis was considered. Several weeks into his admission he developed a lower motor neurone facial nerve palsy. He was treated with antibiotics for an incidental finding of a hospital-acquired pneumonia on imaging, which remarkably led to the resolution of his facial palsy and allowed a dramatic reduction in analgesia. This triggered further investigations; identifying Lyme neuroborreliosis as the cause of his symptoms.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Back Pain/etiology , Facial Paralysis/etiology , Lyme Neuroborreliosis/diagnosis , Humans , Lyme Neuroborreliosis/complications , Lyme Neuroborreliosis/drug therapy , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
The use of annealing in forensic glass casework is reviewed. New data is presented that suggests a continuous approach to the interpretation of such data may be superior to the classification approach. Data are presented supporting the previously observed relationship between change in refractive index (RI) and the thickness of the glass pane. An examination of the possible assumption of independence between RI and change in RI is undertaken.
