The Power of Single‐Cell Analysis for the Study of Liver Pathobiology

Chu, Angela; Schilling, Joel D.; King, Kevin R.; Feldstein, Ariel E.

doi:10.1002/hep.31485

Cited by 22 publications

(18 citation statements)

References 53 publications

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“…The contractile activity of aHSCs is characterized by the expression of alpha smooth muscle actin (αSMA; encoded by Acta2 ) and S100a6 (S100 calcium-binding protein A6), the formation of stress fibers, and the deposition of ECM components [ 28 ]. Fibrillary collagens (e.g., collagen type I, which is encoded by Col1a1 and Col1a2 ) in the space of Disse cause sinusoidal capillarization, altering the fenestrated liver sinusoidal endothelial cell (LSEC) phenotype to a more defined vascular basement membrane [ 29 , 30 ].…”

Section: Nafld Etiology and The Role Of Hepatic Stellate Cellsmentioning

confidence: 99%

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

2021

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Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.

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Section: Nafld Etiology and The Role Of Hepatic Stellate Cellsmentioning

confidence: 99%

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

2021

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“…Several cell types have been implicated in liver fibrosis using various methodologies, but the molecular and cellular complexity of the hepatic microenvironment remains a key obstacle hindering the development of potential treatments. [ 5 ] The advent of single‐cell RNA sequencing (scRNAseq) has enabled the identification of specific cellular phenotypes in complex disease, [ 6 ] and recent applications of scRNAseq in patients with cirrhosis has uncovered multiple cell types of mesenchymal, endothelial, and monocytic origin increased in end‐stage disease. [ 7 , 8 ] Despite these advances, scRNAseq is limited by the necessity of single‐cell suspensions that require tissue digestion and homogenization, which prevents the specific localization of gene expression and distinct cells to fibrotic lesions.…”

Section: Introductionmentioning

confidence: 99%

Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis

et al. 2022

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Liver fibrosis and cirrhosis have limited therapeutic options and represent a serious unmet patient need. Recent use of single‐cell RNA sequencing (scRNAseq) has identified enriched cell types infiltrating cirrhotic livers but without defining the microanatomical location of these lineages thoroughly. To assess whether fibrotic liver regions specifically harbor enriched cell types, we explored whether whole‐tissue spatial transcriptomics combined with scRNAseq and gene deconvolution analysis could be used to localize cell types in cirrhotic explants of patients with end‐stage liver disease (total n = 8; primary sclerosing cholangitis, n = 4; primary biliary cholangitis, n = 2, alcohol‐related liver disease, n = 2). Spatial transcriptomics clearly identified tissue areas of distinct gene expression that strongly correlated with the total area (Spearman r = 0.97, p = 0.0004) and precise location (parenchyma, 87.9% mean congruency; range, 73.1%–97.1%; fibrosis, 68.5% mean congruency; range, 41.0%–91.7%) of liver regions classified as parenchymal or fibrotic by conventional histology. Deconvolution and enumeration of parenchymal and fibrotic gene content as measured by spatial transcriptomics into distinct cell states revealed significantly higher frequencies of ACTA2 + FABP4 + and COL3A1 + mesenchymal cells, IL17RA + S100A8 + and FCER1G + tissue monocytes, VCAM1 + SDC3 + Kupffer cells, CCL4 + CCL5 + KLRB1 + and GZMA + IL17RA + T cells and HLA‐DR +, CD37 + CXCR4 + and IGHM + IGHG + B cells in fibrotic liver regions compared with parenchymal areas of cirrhotic explants. Conclusion : Our findings indicate that spatial transcriptomes of parenchymal and fibrotic liver regions express unique gene content within cirrhotic liver and demonstrate proof of concept that spatial transcriptomes combined with additional RNA sequencing methodologies can refine the localization of gene content and cell lineages in the search for antifibrotic targets.

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“…The unique insight such techniques can provide in addition to RNA-based analyses has been discussed well by Shema et al [ 93 ]. In general, single-cell transcriptomics have been reviewed extensively in recent years [ 94 , 95 , 96 , 97 ], and we refer to these for further insight.…”

Section: Emerging Technologies To Analyze the Cis-regulatory Genome A...mentioning

confidence: 99%

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

Dam

Toft

Grøntved

2022

Cells

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver.

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The Power of Single‐Cell Analysis for the Study of Liver Pathobiology

Cited by 22 publications

References 53 publications

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

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