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Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

Research output: Contribution to journalArticle

  • J R Wilson-Kanamori
  • James Smith
  • Jordan Portman
  • Karolina Wallenborg
  • Simone Picelli
  • A Zagórska
  • Swetha V Pendem
  • Thomas E Hudson
  • Minnie M Wu
  • Grant R Budas
  • David G Breckenridge
  • Ewan Harrison
  • S A Teichmann
  • J C Marioni

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Original languageEnglish
Pages (from-to)1832-1847.e8
JournalCell Reports
Volume29
Issue number7
Early online date12 Nov 2019
DOIs
Publication statusE-pub ahead of print - 12 Nov 2019

Abstract

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.

ID: 116675129