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

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.

SUBMITTER: Dobie R

PROVIDER: S-EPMC6856722 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Dobie Ross R Wilson-Kanamori John R JR Henderson Beth E P BEP Smith James R JR Matchett Kylie P KP Portman Jordan R JR Wallenborg Karolina K Picelli Simone S Zagorska Anna A Pendem Swetha V SV Hudson Thomas E TE Wu Minnie M MM Budas Grant R GR Breckenridge David G DG Harrison Ewen M EM Mole Damian J DJ Wigmore Stephen J SJ Ramachandran Prakash P Ponting Chris P CP Teichmann Sarah A SA Marioni John C JC Henderson Neil C NC

Cell reports 20191101 7

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 in ...[more]

PMID: 31722201

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Project description:BackgroundThe contributions of various types of cell populations in dialysis-related peritoneal fibrosis are poorly understood. Single-cell RNA sequencing brings single-cell level resolution to the analysis of cellular transcriptomics, which provides a new way to further characterize the distinct roles and functional states of each cell population during peritoneal fibrosis.MethodsSingle-cell transcriptomics from normal peritoneal tissues of six patients, from effluent of patients with short-term peritoneal dialysis (less than 2 weeks, n = 6), and from long-term peritoneal dialysis patients (more than 6 years, n = 4) were analyzed.ResultsWe identified a distinct cell component between samples among different groups. Functional analysis of the differentially expressed genes identified cell type specific biological processes relevant to different fibrosis stages. Well-known key molecular mechanisms participating in the pathophysiology of peritoneal fibrosis were vitrified, and some of them were found to be restricted to specific cell types. Gradually growing enrichment of PI3K/AKT/mTOR pathway and impairment of oxidative phosphorylation in mesothelial cells and fibroblasts were found from healthy control, short-term dialysis, to long-term dialysis, respectively. The fibroblasts' population obtained from the patients, who received peritoneal dialysis, showed a functional characteristic of immune-chemotaxis and immune response, which was characterized by broadly significant increase in the expression of interleukins, chemokines, cytokines, and human leukocyte antigens. Furthermore, we described the intercellular crosstalk networks based on receptor-ligand interactions, and highlighted a central role of fibroblasts in regulating the key mechanisms of peritoneal fibrosis through crosstalk with other cells.ConclusionsIn summary, despite describing information for fibrogenic molecular mechanisms in the resolution level of individual cell populations, this work identifies the significant functional evolution of fibroblasts during peritoneal fibrosis. This study also reveals the intercellular receptor-ligand interactions in which the fibroblasts serve as a major node, eventually providing new insights into the role of fibroblasts during disease pathogenesis.

Dataset Information

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

Publications

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

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