Cell Reports
Volume 29, Issue 7, 12 November 2019, Pages 1832-1847.e8
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Article
Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

https://doi.org/10.1016/j.celrep.2019.10.024Get rights and content
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Highlights

  • scRNA-seq reveals spatial zonation of hepatic stellate cells (HSCs)

  • HSCs partition into topographically diametric lobule regions

  • Functional zonation of HSCs during centrilobular injury-induced fibrosis is uncovered

  • LPAR1 is a therapeutic target on pathological central vein-associated HSC

Summary

Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.

Keywords

liver fibrosis
mesenchyme
hepatic stellate cells
single-cell RNA sequencing
zonation

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These authors contributed equally

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