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

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.

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

“…GEO (https://www.ncbi.nlm.nih.gov/geo/) or Human Cell Atlas (https://www.humancellatlas.org). Totally, we curated single cell gene expression matrices of 13 human tissues, including lung [8], liver [9], ileum [10], rectum [10], blood [11], bone marrow [12], skin [13], spleen [14], esophagus [14], colon [15], eye [16], stomach [17] and kidney [18] (Table S1). For each tissue, we performed cell clustering and dimension reduction on the scaled gene expression matrix using Seurat package [19].…”

Taming the Savage Breast From Within: Transcription Factor 21, a Regulator of Stellate Cell Deactivation

“…In both murine models, Tcf21 expression was reduced under conditions where HSCs are activated, a finding we verified (data not shown) using recently published HSC single-cell RNA-sequencing data sets. (9,10) Moreover, TCF21 levels were restored in a fraction of deactivated HSCs following fibrosis regression in the chronic CCl 4 model, suggesting a strong correlation between TCF21 expression and HSC quiescence.…”

“…Exciting single-cell sequencing studies of liver cell populations further reinforce the heterogeneity and plasticity of macrophage subsets in rodent models and human disease. (9,10) However, the normalization of liver architecture by overexpression of a transcription factor, TCF21, in HSCs refocuses attention on this cell type in not only driving fibrosis but also restoring the liver's architecture once injury subsides. This finding underscores the importance in future studies of identifying restorative mediators secreted by HSCs and how they interact with other resident liver cells, especially sinusoidal endothelial cells, hepatocytes, as well as resident macrophages and infiltrating monocytes.…”

The Transcriptome of Hepatic Fibrosis Revealed by Single‐Cell RNA Sequencing

“…(3) Additionally, in a parallel Cell Reports paper, the same group verified hepatic stellate cell (HSC) subpopulation zonation within the murine fibrotic niche using scRNAseq. (4) scRNAseq has emerged as a powerful methodology to link genotype with phenotype and reveal transcriptional culprits of diseases. Starting from a range of platforms such as smaller-scale laser capture microdissection to larger-scale flow-activated cell sorting (FACS) and microfluidics, RNAseq applied to individual cells can be used to identify cellular subpopulations, unfold the history of a cell's transcriptome (pseudotime reconstruction), and reconstruct gene regulatory networks.…”

“…(3) In a complementary study, this group further orders the topographical distribution of HSCs into subpopulations within the fibrotic niche of the carbon tetrachloride murine model of centrilobular fibrosis using scRNAseq, finding that central vein-associated HSCs (expressing ADAM metallopeptidase with thrombospondin like 2 and R-spondin 3) produce more collagen than portal vein-associated HSCs (expressing nerve growth factor receptor and integrin subunit beta 3). (4) Whether portal vein-associated HSCs produce the majority of collagen in periportal models of liver injury remains to be determined.…”