Resolving the fibrotic niche of human liver cirrhosis at single-cell level.
Animals
Case-Control Studies
Cell Lineage
Duffy Blood-Group System
/ metabolism
Endothelial Cells
/ metabolism
Female
Hepatic Stellate Cells
/ cytology
Hepatocytes
/ cytology
Humans
Liver
/ cytology
Liver Cirrhosis
/ genetics
Macrophages
/ metabolism
Male
Membrane Glycoproteins
/ metabolism
Membrane Proteins
/ metabolism
Mice
Phenotype
Receptor, Platelet-Derived Growth Factor alpha
/ metabolism
Receptors, Cell Surface
/ metabolism
Receptors, Immunologic
/ metabolism
Single-Cell Analysis
Tetraspanin 29
/ metabolism
Transcriptome
Transendothelial and Transepithelial Migration
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
04
09
2018
accepted:
04
09
2019
pubmed:
10
10
2019
medline:
22
4
2020
entrez:
10
10
2019
Statut:
ppublish
Résumé
Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
Identifiants
pubmed: 31597160
doi: 10.1038/s41586-019-1631-3
pii: 10.1038/s41586-019-1631-3
pmc: PMC6876711
mid: EMS84316
doi:
Substances chimiques
ACKR1 protein, human
0
Duffy Blood-Group System
0
Membrane Glycoproteins
0
Membrane Proteins
0
PLVAP protein, human
0
Receptors, Cell Surface
0
Receptors, Immunologic
0
TREM2 protein, human
0
Tetraspanin 29
0
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
512-518Subventions
Organisme : Medical Research Council
ID : MC_PC_17159
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15049
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RM/17/3/33381
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15041
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N022556/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/18/5/34216
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600033
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N008340/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P008887/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1002033
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15075
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/15
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12008/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G84/6205
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 103749
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Références
Marcellin, P. & Kutala, B. K. Liver diseases: a major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 38 (Suppl. 1), 2–6 (2018).
pubmed: 29427496
doi: 10.1111/liv.13682
Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–97.e10 (2015).
pubmed: 25935633
doi: 10.1053/j.gastro.2015.04.043
Ramachandran, P. & Henderson, N. C. Antifibrotics in chronic liver disease: tractable targets and translational challenges. Lancet Gastroenterol. Hepatol. 1, 328–340 (2016).
pubmed: 28404203
doi: 10.1016/S2468-1253(16)30110-8
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).
pubmed: 29967350
pmcid: 6553468
doi: 10.1038/s41591-018-0104-9
Stubbington, M. J. T., Rozenblatt-Rosen, O., Regev, A. & Teichmann, S. A. Single-cell transcriptomics to explore the immune system in health and disease. Science 358, 58–63 (2017).
pubmed: 28983043
pmcid: 5654495
doi: 10.1126/science.aan6828
Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
pubmed: 15630444
pmcid: 539199
doi: 10.1172/JCI200522675
Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012).
pubmed: 23100531
pmcid: 3503234
Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1
doi: 10.1002/hep.22950
pubmed: 19554540
Minutti, C. M. et al. Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356, 1076–1080 (2017).
pubmed: 28495878
pmcid: 5737834
doi: 10.1126/science.aaj2067
Pradere, J.-P. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461–1473 (2013).
pubmed: 23553591
doi: 10.1002/hep.26429
Henderson, N. C. et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc. Natl Acad. Sci. USA 103, 5060–5065 (2006).
pubmed: 16549783
doi: 10.1073/pnas.0511167103
pmcid: 1458794
Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).
pubmed: 19441102
doi: 10.1002/hep.22952
Syn, W. K. et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, 106–115 (2011).
pubmed: 20967826
doi: 10.1002/hep.23998
Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
pubmed: 26813785
pmcid: 4737801
doi: 10.1038/ncomms10321
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
pubmed: 25470051
doi: 10.1038/nature13989
Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).
pubmed: 27492475
pmcid: 5066309
doi: 10.1126/science.aaf4238
La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).
pubmed: 30089906
pmcid: 6130801
doi: 10.1038/s41586-018-0414-6
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
pubmed: 29608179
pmcid: 6700744
doi: 10.1038/nbt.4096
Schelker, M. et al. Estimation of immune cell content in tumour tissue using single-cell RNA-seq data. Nat. Commun. 8, 2032 (2017).
pubmed: 29230012
pmcid: 5725570
doi: 10.1038/s41467-017-02289-3
Ahrens, M. et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 18, 296–302 (2013).
pubmed: 23931760
doi: 10.1016/j.cmet.2013.07.004
Pruenster, M. et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat. Immunol. 10, 101–108 (2009).
pubmed: 19060902
doi: 10.1038/ni.1675
Shetty, S., Weston, C. J., Adams, D. H. & Lalor, P. F. A flow adhesion assay to study leucocyte recruitment to human hepatic sinusoidal endothelium under conditions of shear stress. J. Vis. Exp. 85, 51330 (2014).
Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297–E3305 (2014).
pubmed: 25074909
doi: 10.1073/pnas.1400062111
pmcid: 4136601
Henderson, N. C. et al. Targeting of α
pubmed: 24216753
doi: 10.1038/nm.3282
De Minicis, S. et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 132, 1937–1946 (2007).
pubmed: 17484886
doi: 10.1053/j.gastro.2007.02.033
Mederacke, I., Dapito, D. H., Affò, S., Uchinami, H. & Schwabe, R. F. High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat. Protocols 10, 305–315 (2015).
pubmed: 25612230
doi: 10.1038/nprot.2015.017
Vento-Tormo, R. et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563, 347–353 (2018).
pubmed: 30429548
doi: 10.1038/s41586-018-0698-6
Minutti, C. M. et al. A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation. Immunity 50, 645–654.e6 (2019).
pubmed: 30770250
pmcid: 6436929
doi: 10.1016/j.immuni.2019.01.008
Searle, B. C., Gittelman, R. M., Manor, O. & Akey, J. M. Detecting sources of transcriptional heterogeneity in large-scale RNA-seq data sets. Genetics 204, 1391–1396 (2016).
pubmed: 27729424
pmcid: 5161273
doi: 10.1534/genetics.116.193714
Bain, C. C. et al. Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat. Commun. 7, 11852 (2016).
pubmed: 27292029
pmcid: 4910019
doi: 10.1038/ncomms11852
Heinrich, M. C. et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin. Cancer Res. 18, 4375–4384 (2012).
pubmed: 22745105
doi: 10.1158/1078-0432.CCR-12-0625
Patten, D. A. et al. SCARF-1 promotes adhesion of CD4
pubmed: 29242513
pmcid: 5730566
doi: 10.1038/s41598-017-17928-4
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
pubmed: 22743772
doi: 10.1038/nmeth.2019
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
pubmed: 29203879
pmcid: 5715110
doi: 10.1038/s41598-017-17204-5
Arganda-Carreras, I. et al. Trainable Weka Segmentation: a machine learning tool for microscopy pixel classification. Bioinformatics 33, 2424–2426 (2017).
pubmed: 28369169
doi: 10.1093/bioinformatics/btx180
Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).
pubmed: 15915461
doi: 10.1002/hep.20701
Deroulers, C. et al. Analyzing huge pathology images with open source software. Diagn. Pathol. 8, 92 (2013).
pubmed: 23829479
pmcid: 3706353
doi: 10.1186/1746-1596-8-92
Kendall, T. J. et al. Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease. Histopathology 73, 90–100 (2018).
pubmed: 29464815
pmcid: 6033111
doi: 10.1111/his.13499
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).
pubmed: 25867923
pmcid: 4430369
doi: 10.1038/nbt.3192
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
pubmed: 29144463
pmcid: 6022292
doi: 10.1038/nature24489
Li, W. V. & Li, J. J. An accurate and robust imputation method scImpute for single-cell RNA-seq data. Nat. Commun. 9, 997 (2018).
pubmed: 29520097
pmcid: 5843666
doi: 10.1038/s41467-018-03405-7
Camp, J. G. et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 546, 533–538 (2017).
pubmed: 28614297
doi: 10.1038/nature22796
Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).
pubmed: 24658644
pmcid: 4122333
doi: 10.1038/nbt.2859
McCarthy, D. J., Campbell, K. R., Lun, A. T. L. & Wills, Q. F. Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. Bioinformatics 33, 1179–1186 (2017).
pubmed: 28088763
pmcid: 5408845
Zhang, H. M. et al. AnimalTFDB 2.0: a resource for expression, prediction and functional study of animal transcription factors. Nucleic Acids Res. 43, D76–D81 (2015).
pubmed: 25262351
doi: 10.1093/nar/gku887
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).
pubmed: 28991892
pmcid: 5937676
doi: 10.1038/nmeth.4463
Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015).
pubmed: 25822800
pmcid: 4739640
doi: 10.1038/nmeth.3337