Liver macrophages in health and disease

Immunity, Год журнала: 2022, Номер 55(9), С. 1515 - 1529

Опубликована: Сен. 1, 2022

Язык: Английский

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Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2024, Номер 19(1), С. 453 - 478

Опубликована: Янв. 24, 2024

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance animal models, APAP mechanistically studied drug. This review covers intracellular signaling events starting with metabolism and central role mitochondrial dysfunction involving oxidant stress peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, point no return for cell death. In addition, adaptive mechanisms that limit death are discussed including autophagy, morphology changes, biogenesis. Extensive evidence supports oncotic necrosis as mode death; however, a partial overlap apoptosis, ferroptosis, pyroptosis basis controversial discussions. Furthermore, an update on sterile inflammation injury repair activation Kupffer cells, monocyte-derived macrophages, neutrophils provided. Understanding these led to discovery N-acetylcysteine recently fomepizole effective antidotes against toxicity.

Язык: Английский

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Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers

Cell stem cell, Год журнала: 2023, Номер 30(3), С. 283 - 299.e9

Опубликована: Фев. 13, 2023

Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like (LPLCs) in both mice humans, which contribute remarkably to regeneration. However, it remains unknown how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated regionally activated Kupffer but not peripheral monocyte-derived macrophages. Unexpectedly, using vivo screening, the proinflammatory factor IL-6 niche signal repurposed RRG induction via STAT3 activation, drove expression through binding their pre-accessible enhancers. Notably, RRGs were injury-specific rather than embryogenesis-related Collectively, these findings depict inflammation-mediated transcription driving conversion a progenitor phenotype.

Язык: Английский

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Multimodal decoding of human liver regeneration

Nature, Год журнала: 2024, Номер 630(8015), С. 158 - 165

Опубликована: Май 1, 2024

Abstract The liver has a unique ability to regenerate 1,2 ; however, in the setting of acute failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency transplantation as only curative option 3–5 . Here, advance understanding human regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling healthy and ALF explant livers generate single-cell, pan-lineage atlas regeneration. We uncover novel ANXA2 + migratory hepatocyte subpopulation, which emerges during corollary subpopulation mouse model acetaminophen (APAP)-induced Interrogation necrotic wound closure proliferation across multiple timepoints following APAP-induced injury mice demonstrates that precedes proliferation. Four-dimensional intravital imaging identifies motile hepatocytes at edge area, enabling collective migration sheet effect closure. Depletion reduces growth factor-induced vitro, abrogates injury. Together, our work dissects unanticipated aspects demonstrating an uncoupling uncovering mediates Therapies designed promote rapid reconstitution normal hepatic microarchitecture reparation gut–liver barrier may new areas therapeutic discovery medicine.

Язык: Английский

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Acquisition of epithelial plasticity in human chronic liver disease

Nature, Год журнала: 2024, Номер 630(8015), С. 166 - 173

Опубликована: Май 22, 2024

Abstract For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms becoming well characterized 1–4 , but technical challenges ethical aspects limiting the validation of these results humans. We decided to address this difficulty with respect liver. This organ displays remarkable ability regenerate after acute injury, although liver context recurring injury be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 biopsies from patients different stages metabolic dysfunction-associated steatotic establish cellular map progression. then combined single-cell-level data advanced 3D imaging reveal profound changes architecture. Hepatocytes lose zonation considerable reorganization biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes cholangiocytes without presence stem cells or developmental progenitor activation. Detailed analyses functional validations using cholangiocyte organoids confirm importance PI3K–AKT–mTOR pathway process, thereby connecting acquisition plasticity insulin signalling. Together, indicate creates an environment induces understanding process could open new therapeutic avenues management diseases.

Язык: Английский

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Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair

Immunity, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Our understanding of the functional heterogeneity resident versus recruited macrophages in diseased liver is limited. A population lipid-associated (LAMs) has been reported to populate alongside Kupffer cells (KCs). However, precise roles these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs multiple models injury. Moreover, found that this phenotype not specific macrophages, as a subset KCs can also adopt LAM-like mouse and human liver. By combining genetic targeting populations, determined both play crucial tissue repair. Specifically, triggering receptor expressed on myeloid 2 (TREM2) expression either or required for efficient clearance dying cells, enhancing repair preventing exacerbated fibrosis.

Язык: Английский

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Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 8, 2025

Язык: Английский

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Integrated bioinformatics and multi-omics to investigate the mechanism of Rhododendron molle Flos-induced hepatotoxicity

Journal of Ethnopharmacology, Год журнала: 2025, Номер 341, С. 119308 - 119308

Опубликована: Янв. 1, 2025

Язык: Английский

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Innate immune cells link dietary cues to normal and abnormal metabolic regulation

Nature Immunology, Год журнала: 2025, Номер 26(1), С. 29 - 41

Опубликована: Янв. 1, 2025

Язык: Английский

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Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b

Cell Reports Medicine, Год журнала: 2022, Номер 3(10), С. 100754 - 100754

Опубликована: Окт. 1, 2022

The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role β-catenin. Using single-cell analysis, we identified a conserved Wnt2 Wnt9b expression in endothelial cells (ECs) zone 3. EC-elimination led to both loss β-catenin targets 3, re-appearance 1 genes unraveling dynamicity the LZ process. Impaired LR observed knockouts phenocopied models defective hepatic Wnt signaling. Administration tetravalent antibody activate signaling rescued induced 3 gene controls. agonist also promoted acetaminophen overdose acute failure (ALF) fulfilling unmet clinical need. Overall, report unequivocal EC-Wnt2 show activators as regenerative therapy for ALF.

Язык: Английский

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