2. Academic Validation
  3. Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

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

  • Cell Rep. 2019 Nov 12;29(7):1832-1847.e8. doi: 10.1016/j.celrep.2019.10.024.
Ross Dobie 1,  John R Wilson-Kanamori 1,  Beth E P Henderson 1,  James R Smith 1,  Kylie P Matchett 1,  Jordan R Portman 1,  Karolina Wallenborg 2,  Simone Picelli 2,  Anna Zagorska 3,  Swetha V Pendem 3,  Thomas E Hudson 3,  Minnie M Wu 3,  Grant R Budas 3,  David G Breckenridge 3,  Ewen M Harrison 4,  Damian J Mole 5,  Stephen J Wigmore 5,  Prakash Ramachandran 1,  Chris P Ponting 6,  Sarah A Teichmann 7,  John C Marioni 8,  Neil C Henderson 9
Affiliations

Affiliations

  • 1 Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh EH16 4TJ, UK.
  • 2 Karolinska Institutet (KI), Science for Life Laboratory, Tomtebodavägen 23, Solna 171 65, Sweden.
  • 3 Gilead Sciences, Foster City, CA 94404, USA.
  • 4 Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
  • 5 Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh EH16 4TJ, UK; Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
  • 6 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh EH4 2XU, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 7 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge CB10 1SD, UK; Theory of Condensed Matter Group, The Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, UK.
  • 8 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge CB10 1SD, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
  • 9 Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address: [email protected].
PMID: 31722201 DOI: 10.1016/j.celrep.2019.10.024
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.

Keywords

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

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