Liver macrophages in health and disease

Immunity, Journal Year: 2022, Volume and Issue: 55(9), P. 1515 - 1529

Published: Sept. 1, 2022

Language: Английский

---

Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis

Nature, Journal Year: 2022, Volume and Issue: 610(7931), P. 356 - 365

Published: Oct. 5, 2022

Language: Английский

---

Macrophage functional diversity in NAFLD — more than inflammation

Nature Reviews Endocrinology, Journal Year: 2022, Volume and Issue: 18(8), P. 461 - 472

Published: May 9, 2022

Language: Английский

---

Hepatic stellate cells in physiology and pathology

The Journal of Physiology, Journal Year: 2022, Volume and Issue: 600(8), P. 1825 - 1837

Published: March 21, 2022

Hepatic stellate cells (HSCs) comprise a minor cell population in the liver but serve numerous critical functions normal and response to injury. HSCs are primarily known for their activation upon injury producing collagen-rich extracellular matrix fibrosis. In absence of injury, reside quiescent state, which main function appears be storage retinoids or vitamin A-containing metabolites. Less appreciated include amplifying hepatic inflammatory expressing growth factors that development both initiation termination regeneration. Recent single-cell RNA sequencing studies have corroborated earlier indictaing HSC involves diverse array phenotypic alterations identified unique populations. This review serves highlight these many HSCs, briefly describe recent genetic tools will help thoroughly investigate role physiology pathology.

Language: Английский

---

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

Science Immunology, Journal Year: 2023, Volume and Issue: 8(82)

Published: April 7, 2023

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying populations found human fibrotic tissues could lead new treatments for fibrosis. Here, we used liver lung single-cell RNA sequencing datasets identify a subset CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, CD63. In both murine hepatic pulmonary fibrosis, these were enriched at outside edges scarring adjacent activated mesenchymal cells. Neutrophils expressing MMP9, which participates TGF-β1, type 3 cytokines GM-CSF IL-17A coclustered macrophages. vitro, GM-CSF, IL-17A, TGF-β1 drive differentiation monocytes into scar-associated markers. Such differentiated cells degrade collagen IV but not I promote TGF-β1-induced deposition by models blocking or reduced expansion Our work identifies highly specific population assign profibrotic role across species tissues. It further provides strategy unbiased discovery, triage, preclinical validation therapeutic targets based on this fibrogenic population.

Language: Английский

---

Liver zonation, revisited

Hepatology, Journal Year: 2022, Volume and Issue: 76(4), P. 1219 - 1230

Published: Feb. 17, 2022

Abstract The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen nutrient levels across the hepatic lobule. However, recent advances single‐cell genomics technologies, nuclei RNA sequencing, rapidly evolving fields spatial transcriptomic proteomic profiling have greatly increased our understanding liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect at unprecedented resolution this new information should facilitate emergence novel precision medicine‐based therapies for patients disease.

Language: Английский

---

Understanding the cellular interactome of non-alcoholic fatty liver disease

JHEP Reports, Journal Year: 2022, Volume and Issue: 4(8), P. 100524 - 100524

Published: June 15, 2022

Summary

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. steatohepatitis (NASH), which can lead to cirrhosis, has become leading indication for transplantation both Europe and USA. Liver fibrosis consequence sustained, iterative injury, main determinant outcomes NASH. The possesses remarkable inherent plasticity, regress when injurious agent removed, thus providing opportunities alter long-term through therapeutic interventions. Although hepatocyte injury key driver NASH, multiple other cell lineages within hepatic fibrotic niche play major roles perpetuation inflammation, mesenchymal activation, extracellular matrix accumulation as well resolution. constituents this cellular interactome, how various subpopulations interact drive fibrogenesis an area active research. Important components include endothelial cells, macrophages, passaging immune populations myofibroblasts. In review, we will describe rapidly evolving technologies such single-cell genomics, spatial transcriptomics ligand-receptor analyses are transforming our understanding interactome NAFLD/NASH, new, high-resolution information being leveraged develop rational new therapies patients

Language: Английский

---

Friend or foe? The elusive role of hepatic stellate cells in liver cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 647 - 661

Published: Aug. 7, 2023

Language: Английский

---

Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2023, Volume and Issue: 18(1), P. 439 - 466

Published: Jan. 24, 2023

Hepatocytes are the main workers in hepatic factory, managing metabolism of nutrients and xenobiotics, production recycling proteins, glucose lipid homeostasis. Division labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar distributed tasks at an assembly line. This so-called metabolic zonation has both spatial temporal components. Spatial distribution function different lobular zones necessary perform sequential processes assign right environment. Moreover, control align required feeding fasting cycles. Disruption this spatiotemporal organization impairs key with local systemic consequences. Many diseases, such as nonalcoholic steatohepatitis diabetes, associated impaired liver zonation. Recent technological advances shed new light on gene expression networks controlling how their deregulation may be involved a large variety diseases. We summarize current knowledge about consequences pathobiology.

Language: Английский

---

Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 80(5), P. 730 - 743

Published: Jan. 8, 2024

•ScRNA-seq revealed additional macrophage diversity in the NDD (healthy) liver.•CD206+ macrophages PSC liver show reduced responsiveness to stimulation.•CK7+ HNF4A+ transitioning hepatocytes are enriched fibrotic lesions comparison PBC and NDD. BackgroundPrimary sclerosing cholangitis (PSC) is an immune-mediated cholestatic disease characterized by bile retention, biliary tree destruction, progressive fibrosis leading end stage transplantation. There unmet need understand cellular composition of how it underlies pathogenesis. We generated a comprehensive atlas primary (PBC) reference healthy dataset using multiple multi-omic modalities functional validation.MethodsWe employed single-cell (sc) RNA-seq (47,156 cells), single-nucleus (sn) (23,000 nuclei) spatial transcriptomics (1 sample 10x Visium 5 samples with multi-region profiling Nanostring GeoMx Digital Spatial Profiler) profile ecosystem 10 patients PSC. Transcriptomic profiles were compared 24 neurologically deceased donor livers (107,542 cells) controls, 18,240 cells 20,202 nuclei from 3 PBC, publicly available scRNA-seq data uninjured, 2 NAFLD, ALD, 1 samples. Flow cytometry intracellular cytokine staining was performed validate PSC-specific differences immune cell phenotype function.ResultsPSC explants cirrhosis parenchyma prominent periductal contained population expressing cholangiocyte-like phenotype. These surrounded diverse populations, including monocyte-like macrophages, liver-resident circulating natural killer cells. PSC-associated cholangiocytes, hepatic stellate cells, endothelial expressed chemokine transcripts typically involved recruitment. As well, expanded CD4+ T dendritic neutrophils corresponding receptors these chemokines cytokines, suggesting potential Tissue-resident contrast, number exhibited dysfunctional downregulated inflammatory response LPS IFN-Ɣ stimulation.ConclusionsWe present demonstrate hyper-activation exhaustion-like phenotypes myeloid markers chronic expression late-stage lesions. This has expand our understanding complexity inform novel treatment development.Impact ImplicationsPrimary rare inflammation irreparable damage ducts resulting failure. Due limited underlying pathogenesis disease, there remains paucity options. sequenced diseased compare activity, interactions, localization non-immune that lining scar regions transforming into whereas accumulating within scars. Of which contribute tissue repair, immunoregulatory genes demonstrated lack stimulation. may be maintaining could targeted therapeutic drug development. Primary validation. function.

Language: Английский

---