Abstract
SummaryIterative 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.
Highlights
Liver cirrhosis is a major global healthcare burden, with an estimated 844 million people suffering from chronic liver disease worldwide (Marcellin and Kutala, 2018)
Different mesenchymal cell types have been proposed as the predominant source of myofibroblasts following liver injury (Iwaisako et al, 2014; Kisseleva et al, 2006; Li et al, 2013; Mederacke et al, 2013), recent studies suggest that hepatic stellate cells (HSCs), first described by Kupffer in 1876 as vitamin A+ lipid droplet-containing cells that reside in the perisinusoidal space of the liver (Wake, 1971), are the dominant contributors to the myofibroblast pool independent of the etiology of liver fibrosis (Iwaisako et al, 2014; Mederacke et al, 2013)
Given the topographic distribution of these three mesenchymal subpopulations, we labeled them as fibroblasts (FBs), HSCs, and vascular smooth muscle cells (VSMCs), respectively (Figure 1D)
Summary
Liver cirrhosis is a major global healthcare burden, with an estimated 844 million people suffering from chronic liver disease worldwide (Marcellin and Kutala, 2018). An ideal antifibrotic therapy would target the pathogenic collagen-producing cell population without perturbing homeostatic mesenchymal function. Increasing our understanding of the precise cellular and molecular mechanisms regulating liver fibrosis is fundamental to the rational design and development of effective, highly targeted anti-fibrotic therapies for patients with chronic liver disease (Ramachandran and Henderson, 2016; Trautwein et al, 2015). Myofibroblasts are the key source of pathogenic extracellular matrix deposition during hepatic fibrogenesis and have attracted considerable interest as a potential therapeutic target (Dobie and Henderson, 2016; Friedman, 2015; Hinz et al, 2012; Kisseleva, 2017). Since the discovery 35 years ago that HSCs are major collagen-producing cells in the liver (Friedman et al, 1985; de Leeuw et al, 1984), these cells have been regarded as a functionally homogeneous population, with
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