Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis
| Autor: | Stephen J. Wigmore, Kylie P. Matchett, Prakash Ramachandran, Thomas E. Hudson, Swetha Pendem, James Smith, Grant R. Budas, Sarah A. Teichmann, John R. Wilson-Kanamori, John C. Marioni, Neil C. Henderson, Simone Picelli, Jordan R. Portman, David G. Breckenridge, Anna Zagorska, Minnie M. Wu, Chris P. Ponting, Karolina Wallenborg, Ross Dobie, Ewen M Harrison, Damian J. Mole, Beth E. P. Henderson |
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| Přispěvatelé: | Teichmann, Sarah [0000-0002-6294-6366], Marioni, John [0000-0001-9092-0852], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Liver Cirrhosis
0301 basic medicine Mesenchyme Population mesenchyme Mice Transgenic Biology Article single-cell RNA sequencing General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine zonation Fibrosis Hepatic Stellate Cells medicine Animals Humans Lobules of liver Rats Wistar Receptors Lysophosphatidic Acid education lcsh:QH301-705.5 liver fibrosis Liver injury education.field_of_study Regeneration (biology) medicine.disease Rats 3. Good health Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) Hepatic stellate cell Liver function Single-Cell Analysis Transcriptome 030217 neurology & neurosurgery |
| Zdroj: | Dobie, R, Wilson-Kanamori, J R, Henderson, B, Smith, J, Matchett, K, Portman, J, Wallenborg, K, Picelli, S, Zagórska, A, Pendem, S V, Hudson, T E, Wu, M M, Budas, G R, Breckenridge, D G, Harrison, E, Mole, D J, Wigmore, S J, Ramachandran, P, Ponting, C P, Teichmann, S A, Marioni, J C & Henderson, N C 2019, ' Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis ', Cell Reports, vol. 29, no. 7, pp. 1832-1847.e8 . https://doi.org/10.1016/j.celrep.2019.10.024 Cell Reports Cell Reports, Vol 29, Iss 7, Pp 1832-1847.e8 (2019) |
| ISSN: | 2211-1247 |
| Popis: | 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. Graphical Abstract 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 Dobie et al. use scRNA-seq to reveal spatial and functional zonation of hepatic stellate cells (HSCs) across the hepatic lobule, identifying central vein-associated HSCs as the dominant pathogenic collagen-producing cells during centrilobular injury-induced fibrosis. This illustrates the power of scRNA-seq to resolve the key collagen-producing cells driving liver fibrosis. |
| Databáze: | OpenAIRE |
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