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      Resolving the fibrotic niche of human liver cirrhosis at single cell level

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          Abstract

          Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 human single cells, yielding molecular definitions for non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2 +CD9 + macrophage subpopulation, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define novel ACKR1 + and PLVAP + endothelial cells which expand in cirrhosis, are topographically scar-restricted and enhance leucocyte transmigration. Multi-lineage ligand-receptor modelling of interactions between the novel scar-associated macrophages, endothelial cells and PDGFRα + collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.

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          Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.

          Jeremy Duffield, Stuart J Forbes, Christothea M. Constandinou … (2005)
          Macrophages perform both injury-inducing and repair-promoting tasks in different models of inflammation, leading to a model of macrophage function in which distinct patterns of activation have been proposed. We investigated macrophage function mechanistically in a reversible model of liver injury in which the injury and recovery phases are distinct. Carbon tetrachloride---induced liver fibrosis revealed scar-associated macrophages that persisted throughout recovery. A transgenic mouse (CD11b-DTR) was generated in which macrophages could be selectively depleted. Macrophage depletion when liver fibrosis was advanced resulted in reduced scarring and fewer myofibroblasts. Macrophage depletion during recovery, by contrast, led to a failure of matrix degradation. These data provide the first clear evidence that functionally distinct subpopulations of macrophages exist in the same tissue and that these macrophages play critical roles in both the injury and recovery phases of inflammatory scarring.
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            Origin of myofibroblasts in the fibrotic liver in mice.

            Keiko Iwaisako, Chunyan Jiang, Mingjun Zhang … (2014)
            Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl4) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP(+) cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl4 liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.
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              Is Open Access

              Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities

              Calum C. Bain, Catherine Hawley, Hannah Garner … (2016)
              Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80hiGATA6+ macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C+ monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80loMHCII+ cells that act, in part, as precursors of F4/80hiGATA6+ macrophages. Notably, monocyte-derived F4/80hi macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 05 September 2019
                Publication date (Electronic): 09 October 2019
                Publication date (Print): November 2019
                Publication date PMC-release: 09 April 2020
                Volume: 575
                Issue: 7783
                Pages: 512-518
                Affiliations
                [1 ]University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK
                [2 ]NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, UK
                [3 ]Institute of Immunology and Immunotherapy, University of Birmingham, UK
                [4 ]Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK
                [5 ]Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
                [6 ]Division of Pathology, University of Edinburgh, Edinburgh, UK
                [7 ]Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
                [8 ]Office of the Vice Chancellor, Beacon House and National Institute for Health Research, Biomedical Research Centre, Bristol, UK
                [9 ]Department of Hepatology and Gastroenterology, Charité University Medical Center, Berlin, Germany
                [10 ]MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
                [11 ]Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, USA
                [12 ]MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK
                [13 ]European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, UK
                [14 ]Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
                [15 ]Theory of Condensed Matter Group, The Cavendish Laboratory, University of Cambridge, JJ Thomson Ave, Cambridge, CD3 0EH, UK
                Author notes
                [* ]Address correspondence to: Prakash Ramachandran, University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, UK, EH16 4TJ. Phone: 0131.242.6654; Prakash.Ramachandran@ 123456ed.ac.uk or Neil Henderson, University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, UK, EH16 4TJ. Phone: 0131.242.6688; Neil.Henderson@ 123456ed.ac.uk
                Article
                Manuscript ID: EMS84316
                DOI: 10.1038/s41586-019-1631-3
                PMC ID: 6876711
                PubMed ID: 31597160
                SO-VID: 54a27dec-bf92-4336-944b-c7200f2252f6
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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