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

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...

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Autores principales: Ramachandran, P, Dobie, R, Wilson-Kanamori, JR, Dora, EF, Henderson, BEP, Luu, NT, Portman, JR, Matchett, KP, Brice, M, Marwick, JA, Taylor, RS, Efremova, M, Vento-Tormo, R, Carragher, NO, Kendall, TJ, Fallowfield, JA, Harrison, EM, Mole, DJ, Wigmore, SJ, Newsome, PN, Weston, CJ, Iredale, JP, Tacke, F, Pollard, JW, Ponting, CP, Marioni, JC, Teichmann, SA, Henderson, NC
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876711/
https://www.ncbi.nlm.nih.gov/pubmed/31597160
http://dx.doi.org/10.1038/s41586-019-1631-3
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author Ramachandran, P
Dobie, R
Wilson-Kanamori, JR
Dora, EF
Henderson, BEP
Luu, NT
Portman, JR
Matchett, KP
Brice, M
Marwick, JA
Taylor, RS
Efremova, M
Vento-Tormo, R
Carragher, NO
Kendall, TJ
Fallowfield, JA
Harrison, EM
Mole, DJ
Wigmore, SJ
Newsome, PN
Weston, CJ
Iredale, JP
Tacke, F
Pollard, JW
Ponting, CP
Marioni, JC
Teichmann, SA
Henderson, NC
author_facet Ramachandran, P
Dobie, R
Wilson-Kanamori, JR
Dora, EF
Henderson, BEP
Luu, NT
Portman, JR
Matchett, KP
Brice, M
Marwick, JA
Taylor, RS
Efremova, M
Vento-Tormo, R
Carragher, NO
Kendall, TJ
Fallowfield, JA
Harrison, EM
Mole, DJ
Wigmore, SJ
Newsome, PN
Weston, CJ
Iredale, JP
Tacke, F
Pollard, JW
Ponting, CP
Marioni, JC
Teichmann, SA
Henderson, NC
author_sort Ramachandran, P
collection PubMed
description 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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spelling pubmed-68767112020-04-09 Resolving the fibrotic niche of human liver cirrhosis at single cell level Ramachandran, P Dobie, R Wilson-Kanamori, JR Dora, EF Henderson, BEP Luu, NT Portman, JR Matchett, KP Brice, M Marwick, JA Taylor, RS Efremova, M Vento-Tormo, R Carragher, NO Kendall, TJ Fallowfield, JA Harrison, EM Mole, DJ Wigmore, SJ Newsome, PN Weston, CJ Iredale, JP Tacke, F Pollard, JW Ponting, CP Marioni, JC Teichmann, SA Henderson, NC Nature Article 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. 2019-10-09 2019-11 /pmc/articles/PMC6876711/ /pubmed/31597160 http://dx.doi.org/10.1038/s41586-019-1631-3 Text en http://www.nature.com/authors/editorial_policies/license.html#terms 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
spellingShingle Article
Ramachandran, P
Dobie, R
Wilson-Kanamori, JR
Dora, EF
Henderson, BEP
Luu, NT
Portman, JR
Matchett, KP
Brice, M
Marwick, JA
Taylor, RS
Efremova, M
Vento-Tormo, R
Carragher, NO
Kendall, TJ
Fallowfield, JA
Harrison, EM
Mole, DJ
Wigmore, SJ
Newsome, PN
Weston, CJ
Iredale, JP
Tacke, F
Pollard, JW
Ponting, CP
Marioni, JC
Teichmann, SA
Henderson, NC
Resolving the fibrotic niche of human liver cirrhosis at single cell level
title Resolving the fibrotic niche of human liver cirrhosis at single cell level
title_full Resolving the fibrotic niche of human liver cirrhosis at single cell level
title_fullStr Resolving the fibrotic niche of human liver cirrhosis at single cell level
title_full_unstemmed Resolving the fibrotic niche of human liver cirrhosis at single cell level
title_short Resolving the fibrotic niche of human liver cirrhosis at single cell level
title_sort resolving the fibrotic niche of human liver cirrhosis at single cell level
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876711/
https://www.ncbi.nlm.nih.gov/pubmed/31597160
http://dx.doi.org/10.1038/s41586-019-1631-3
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