Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Access Granted
Updated February 14, 2025

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, has a corollary population in mouse liver fibrosis 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.

Prakash RamachandranUniversity of Edinburgh
Neil C HendersonUniversity of Edinburgh
John Roger Wilson-Kanamori1
Prakash Ramachandran1
Neil C Henderson (Principal Investigator)1
Ross Dobie1
Elena F Dora1
Jodran R Portman1
Kylie P Matchett1
Madara Brice1
John A Marwick1
Mirjana Efremova2
Roser Vento-Tormo2
Neil O Carragher1
Tim J Kendall1
Johnathan A Fallowfield1
Ewen M Harrison3
Damian J Mole1
Stephen J Wigmore1
Philip N Newsome4
Chris J Weston4
John P Iredale5
Frank Tacke6
Jeffrey W Pollard7
Chris P Ponting8
John C Marioni2
Sarah A Teichmann2
1University of Edinburgh
2Wellcome Sanger Institute
3University of Edinburgh; Royal Infirmary of Edinburgh
4University of Birmingham
5Office of the Vice Chancellor, Beacon House; National Institute for Health Research Bristol Biomedical Research Centre
6Charité University Medical Center
7The Queen’s Medical Research Institute; University of Edinburgh
8MRC Institute of Genetics and Molecular Medicine; University of Edinburgh
Ami Day

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Atlas

None

Analysis Portals

None

Project Label

HealthyAndCirrhoticLiver

Species

2 species

Sample Type

specimens

Anatomical Entity

2 anatomical entities

Organ Part

Unspecified

Selected Cell Types

3 cell types

Disease Status (Specimen)

6 disease statuses

Disease Status (Donor)

6 disease statuses

Development Stage

2 development stages

Library Construction Method

10X 3' v2 sequencing

Nucleic Acid Source

single cell

Paired End

false

File Format

4 file formats

Cell Count Estimate

100.0k

Donor Count

16
bam26 file(s)fastq.gz156 file(s)loom29 file(s)zip1 file(s)