Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution

Brianna R. Watson, Biplab Paul, Raza Ur Rahman, Liat Amir-Zilberstein, Åsa Segerstolpe, Eliana T. Epstein, Shane Murphy, Ludwig Geistlinger, Tyrone Lee, Angela Shih, Jacques Deguine, Ramnik J. Xavier, Jeffrey R. Moffitt () and Alan C. Mullen ()
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Brianna R. Watson: Boston Children’s Hospital
Biplab Paul: University of Massachusetts Chan Medical School
Raza Ur Rahman: University of Massachusetts Chan Medical School
Liat Amir-Zilberstein: Broad Institute of Harvard and MIT
Åsa Segerstolpe: Broad Institute of Harvard and MIT
Eliana T. Epstein: Massachusetts General Hospital
Shane Murphy: Broad Institute of Harvard and MIT
Ludwig Geistlinger: Harvard Medical School
Tyrone Lee: Harvard Medical School
Angela Shih: Massachusetts General Hospital
Jacques Deguine: Broad Institute of Harvard and MIT
Ramnik J. Xavier: Broad Institute of Harvard and MIT
Jeffrey R. Moffitt: Boston Children’s Hospital
Alan C. Mullen: University of Massachusetts Chan Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions. Finally, MERFISH and snRNA-seq analysis of fibrotic liver samples identify two hepatocyte populations that expand with injury and do not have clear zonal distributions. Together these spatial maps of the healthy and fibrotic liver provide a deeper understanding of the cellular and spatial remodeling that drives disease which, in turn, could provide new avenues for intervention and further study.

Date: 2025
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DOI: 10.1038/s41467-024-55325-4

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