Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Loft, Anne; Alfaro, Ana Jimena; Schmidt, Søren Fisker; Pedersen, Felix Boel; Terkelsen, Mike Krogh; Puglia, Michele; Chow, Kan Kau; Feuchtinger, Annette; Troullinaki, Maria; Maida, Adriano; Wolff, Gretchen; Sakurai, Minako; Berutti, Riccardo; Üstünel, Bilgen Ekim; Nawroth, Peter P.; Ravnskjær, Kim; Díaz, Mauricio Berriel; Blagoev, Blagoy; Herzig, Stephan

doi:10.1016/j.cmet.2021.06.005

Cited by 103 publications

(86 citation statements)

References 82 publications

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“…NAFLD is driven by gene regulatory changes in distinct cell type populations of the liver, emphasizing the importance of studying the disease at cell type resolution. This can be approached by the enrichment of specific cell types prior to the cistromic analysis ( Figure 2 A) [ 12 , 54 , 55 , 56 , 57 ]. Enzyme-based tissue dissociation is a commonly used approach to isolate whole cells from fresh tissues of rodent disease models and human biopsies ( Figure 2 A, right and Figure 2 B).…”

Section: Strategies To Study Cis-regulatory Regions In Individual Cel...mentioning

confidence: 99%

“…A few recent studies have used different genetic-based cell/nucleus enrichment strategies to uncover cis-regulatory regions in different cell types of the liver. These include specific studies of mouse hepatocytes, KCs, macrophages, and HSCs [ 11 , 12 , 55 ]. Each study used very different disease models to study liver tissue remodeling, which should be kept in mind when these studies are compared and related to the bulk liver analysis described above.…”

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

“…Each study used very different disease models to study liver tissue remodeling, which should be kept in mind when these studies are compared and related to the bulk liver analysis described above. Specifically, the hepatocytes were isolated from a mouse model replicating NASH induced by diets promoting steatosis and fibrosis, but without DIO [ 55 ]. KCs/macrophages were enriched from a rodent DIO model developing NASH [ 12 ], whereas the HSCs were isolated from mice treated with CCl 4 , which promotes NASH-like fibrosis without steatosis [ 11 ].…”

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

“…Thus, isolating hepatocytes in samples from NASH mouse models may lead to greater insights into hepatocyte regulatory plasticity in the disease. Recently, Loft and colleagues used the INTACT approach to tag and isolate hepatocyte nuclei in a NASH mouse model and performed ATAC-seq and RNA-seq to investigate gene-regulatory mechanisms during diet-induced steatosis and fibrosis [ 55 ]. ATAC-seq analysis of hepatocyte nuclei showed extensive chromatin remodeling during NASH progression (thousands of regions were dynamically regulated), which to some extent contradicts DNase-seq experiments from whole liver tissue isolated from DIO mice [ 23 ].…”

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

“…ATAC-seq analysis of hepatocyte nuclei showed extensive chromatin remodeling during NASH progression (thousands of regions were dynamically regulated), which to some extent contradicts DNase-seq experiments from whole liver tissue isolated from DIO mice [ 23 ]. DNA motif analysis of the regulated cistrome predicted several TFs to be involved [ 55 ]. For example, motifs predicted to gain activity in the cis-regulatory regions included AP-1 motifs, which have previously been reported to facilitate progression of NAFLD [ 64 ].…”

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

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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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Section: Strategies To Study Cis-regulatory Regions In Individual Cel...mentioning

confidence: 99%

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

Section: The Cis-regulatory Genome In Specific Cell Populations Of Th...mentioning

confidence: 99%

See 3 more Smart Citations

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

Dam

Toft

Grøntved

2022

Cells

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Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis

Zhang,

Deng,

Huang

et al. 2024

Advanced Materials

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During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs) and dysfunctional hepatocytes constructs a self‐amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single‐cell centric treatment approaches showed unsatisfactory efficacy and failed to meet clinical demand. Herein, a vicious cycle‐breaking strategy was proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate modified and vismodegib loaded nanoparticles (CS‐NPs/VDG) were designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid modified and silybin loaded nanoparticles (GA‐NPs/SIB) were prepared to restore hepatocytes function by relieving oxidative stress. The results showed successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multi‐regulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing anti‐fibrotic regimens.This article is protected by copyright. All rights reserved

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Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

2022

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Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease.Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

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Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Cited by 103 publications

References 82 publications

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

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

Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis

Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

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