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

作者：Ross Dobie, John R. Wilson‐Kanamori, Beth E. P. Henderson, James R. Smith, Kylie P. Matchett, Jordan R. Portman, Karolina Wallenborg, Simone Picelli, Anna Zagórska, Swetha Pendem, Thomas E. Hudson, Minnie M. Wu, Grant R. Budas, David G. Breckenridge, Ewen Munro Harrison, Damian J. Mole, Stephen J. Wigmore, Prakash Ramachandran, Chris Paul Ponting, Sarah Amalia Teichmann, John C. Marioni, Neil Cowan Henderson · 发表于：Cell Reports · 年份：2019 · DOI：10.1016/j.celrep.2019.10.024 · 被引用次数：446 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Phagocytosis and Immune Regulation

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.