Novel Insights on Notch signaling pathways in liver fibrosis

Ni, Ming-ming; Wang, Ya-Rui; Wu, Wenwen; Xia, Chong-cai; Zhang, Yihe; Xu, Jing; Xu, Tao; Li, Jun

doi:10.1016/j.ejphar.2018.02.051

Cited by 56 publications

(47 citation statements)

References 95 publications

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“…Scar-associated macrophages are enriched for regulons containing the transcription factors HES1 and EGR2 (Extended Data Fig. 5f, g), both of which have been associated with modulation of macrophage phenotype and tissue fibrosis [40][41][42][43] .…”

Section: Fibrogenic Phenotype Of Scar-associated Macrophagesmentioning

confidence: 99%

“…7h). Notch signalling regulates myofibroblast phenotype and tissue fibrosis43 , whilst arterial Notch ligand expression regulates monocyte-derived macrophage differentiation and macrophage function in tissue repair69 . In keeping with active Notch signalling in SAMs, we demonstrate upregulation of the transcription factor regulon HES1, a key downstream target of Notch(Fig.…”

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confidence: 99%

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Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Ramachandran

Dobie

Wilson-Kanamori

et al. 2019

Preprint

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Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2 + CD9 + macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1 + and PLVAP + endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis. MainLiver cirrhosis is a major global healthcare burden. Recent estimates suggest that 844 million people worldwide have chronic liver disease, with a mortality rate of two million deaths per year and a rising incidence 1 . In health, the liver serves a myriad of functions including detoxification, metabolism, bile production and immune surveillance. Chronic liver disease, the result of iterative liver injury secondary to any cause, results in progressive fibrosis, disrupted hepatic architecture, vascular changes and aberrant regeneration, defining characteristics of liver cirrhosis 2 . Importantly, the degree of liver fibrosis predicts adverse patient outcomes, including the development of cirrhosis-related complications, hepatocellular carcinoma and death 3 . Hence, there is a clear therapeutic imperative to develop effective anti-fibrotic approaches for patients with chronic liver disease 4-7 .Liver fibrosis involves a complex, orchestrated interplay between multiple nonparenchymal cell (NPC) lineages including immune, endothelial and mesenchymal cells spatially located within areas of scarring, termed the fibrotic niche. Despite rapid progress in our understanding of the cellular interactions underlying liver fibrogenesis accrued using rodent models, there remains a significant 'translational gap' between putative targets and effective patient therapies 4,5 . This is in part due to the very limited definition of the functional heterogeneity and interactome of cell lineages that contribute to the fibrotic niche of human liver cirrhosis, which is imperfectly recapitulated by rodent models 4,6 .Single-cell RNA sequencing (scRNA-seq) has the potential to deliver a step change in both our understanding of healthy tissue homeostasis as well as disease pathogenesis, allowing the interr...

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Section: Fibrogenic Phenotype Of Scar-associated Macrophagesmentioning

confidence: 99%

mentioning

confidence: 99%

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Ramachandran

Dobie

Wilson-Kanamori

et al. 2019

Preprint

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“…Liver fibrosis, the accumulation of excessive extracellular matrix (ECM) in the liver parenchyma, is one main predictor for most chronic liver diseases (Ni et al., 2018). Hepatic stellate cells (HSCs) have a crucial role in liver fibrosis development (Puche, Saiman, & Friedman, 2013).…”

Section: Introductionmentioning

confidence: 99%

Malvidin induces hepatic stellate cell apoptosis via the endoplasmic reticulum stress pathway and mitochondrial pathway

Zhang

et al. 2020

Food Science & Nutrition

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Blueberries have great beneficial effects due to high level of anthocyanins, especially malvidin. Hepatic stellate cells (HSCs) can be activated and increase excessive extracellular matrix (ECM) components, which play a central role in liver fibrogenesis. Therefore, activated HSC’s apoptosis can be induced to recover liver fibrosis. Malvidin's effects on apoptosis in rat activated hepatic stellate T6 cells (HSC‐T6) in vitro were investigated here. High concentration of malvidin was found to significantly induce apoptosis, activate caspase‐3, increase malondialdehyde, upregulate Bax, but downregulate Bcl‐2. Moreover, malvidin upregulated the protein levels of some endoplasmic reticulum stress (ERS)‐typical markers, including caspase‐12, glucose‐regulated protein 78 (GRP78), and CCAAT/enhancer‐binding protein (C/EBP) homologous protein (CHOP), suggesting that malvidin induced HSC apoptosis by the ERS apoptosis pathway as well as the mitochondrial‐dependent pathway. These findings indicated that blueberry anthocyanins, especially malvidin, could induce activated hepatic stellate cell apoptosis and might act as one kind of functional food ingredient or a novel nutraceutical beneficial for liver health.

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“…In this review, we provide a focused update on the impact of cellular metabolism on HSC activation and fibrogenesis. A detailed discussion on other signals and pathways is beyond the scope of this article and has been reviewed elsewhere ( Weiskirchen and Tacke, 2014 ; Lee et al, 2015 ; Wallace et al, 2015 ; Yang and Seki, 2015 ; El Taghdouini and van Grunsven, 2016 ; Hyun and Jung, 2016 ; Nwosu et al, 2016 ; Schumacher and Guo, 2016 ; de Oliveira da Silva et al, 2017 ; Higashi et al, 2017 ; Huang et al, 2017 ; Jiang et al, 2017 ; Kisseleva, 2017 ; Tsuchida and Friedman, 2017 ; Mortezaee, 2018 ; Ni et al, 2018 ; Wang J. N. et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Hou

Syn

2018

Front. Cell Dev. Biol.

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Activation of hepatic stellate cell (HSC) involves the transition from a quiescent to a proliferative, migratory, and fibrogenic phenotype (i.e., myofibroblast), which is characteristic of liver fibrogenesis. Multiple cellular and molecular signals which contribute to HSC activation have been identified. This review specially focuses on the metabolic changes which impact on HSC activation and fibrogenesis.

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Novel Insights on Notch signaling pathways in liver fibrosis

Cited by 56 publications

References 95 publications

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Malvidin induces hepatic stellate cell apoptosis via the endoplasmic reticulum stress pathway and mitochondrial pathway

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

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