Heterogeneity of hepatic stellate cells in a mouse model of non‐alcoholic steatohepatitis (NASH)

Published on Feb 7, 2021in Hepatology17.425
· DOI :10.1002/HEP.31743
Sara Brin Rosenthal16
Estimated H-index: 16
(UCSD: University of California, San Diego),
Xiao Liu36
Estimated H-index: 36
(UCSD: University of California, San Diego)
+ 8 AuthorsDavid A. Brenner150
Estimated H-index: 150
(UCSD: University of California, San Diego)
Source
Abstract
In clinical and experimental non-alcoholic steatohepatitis (NASH), the origin of the scar-forming myofibroblast is the hepatic stellate cell (HSC). We used foz/foz mice on a Western diet to characterize in detail the phenotypic changes of HSCs in a NASH model. We examined the single cell expression profiles (scRNA-Seq) of HSCs purified from the normal livers of foz/foz mice on a chow diet, in NASH with fibrosis of foz/foz mice on a Western diet, and in livers during regression of NASH after switching back to a chow diet. Selected genes were analyzed using immunohistochemistry, qRT-PCR, and shRNA-knockdown in primary mouse HSCs. Our analysis of the normal liver identified two distinct clusters of quiescent HSCs that correspond to their acinar position of either pericentral vein or periportal vein. The NASH livers had four distinct HSC clusters, including one representing the classic fibrogenic myofibroblast. The three other HSC clusters consisted of a proliferating cluster, an intermediate activated cluster, and an immune and inflammatory cluster. The livers with NASH regression had one cluster of inactivated HSCs, which was similar to, but distinct from, the quiescent HSCs. Conclusion: Analysis of scRNA-Seq in combination with an interrogation of previous studies has revealed an unanticipated heterogeneity of HSC phenotypes under normal and injured states.
References38
Newest
#1Prakash Ramachandran (Edin.: University of Edinburgh)H-Index: 19
#2Kylie P. Matchett (Edin.: University of Edinburgh)H-Index: 6
Last. Neil C. Henderson (Edin.: University of Edinburgh)H-Index: 36
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Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these tec...
Source
#1Richard Barrett (UPenn: University of Pennsylvania)H-Index: 3
#2Ellen Puré (UPenn: University of Pennsylvania)H-Index: 64
: Immune-targeted approaches are rapidly changing the therapeutic landscape for cancer. In spite of that, most patients show resistance or acquire resistance to these therapies. Increasing work describing the tumor microenvironment (TME) has highlighted this space as one of the key determinants in tumor immune response and immunotherapeutic success. Frequently overlooked within this space, cancer-associated fibroblasts (CAFs) within the TME have surfaced as an important dictator of the tumor imm...
Source
#1Abdel Nasser Hosein (UTSW: University of Texas Southwestern Medical Center)H-Index: 3
#2Rolf A. Brekken (UTSW: University of Texas Southwestern Medical Center)H-Index: 79
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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-assoc...
Source
#1Xiao Liu (UCSD: University of California, San Diego)H-Index: 36
#2Jun Xu (UCSD: University of California, San Diego)H-Index: 74
Last. Tatiana Kisseleva (UCSD: University of California, San Diego)H-Index: 50
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Abstract Background & Aims Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (qHSCs) into collagen type I-producing myofibroblasts (activated or aHSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of aHSCs/myofibroblasts into a quiescent-like state (iHSCs). We aimed identify molecular features of phenotypes of HSCs from mice and humans. Methods We performed studies with LratCre, Ets1-floxed, Nf1-floxed, Pparγ-floxe...
Source
#1Xuelian Xiong (Fudan University)H-Index: 5
#2Henry Kuang (UM: University of Michigan)H-Index: 4
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The liver contains heterogeneous cell types that exhibit distinct spatial, molecular, and functional properties. The cells in the liver communicate with each other via a network of ligands and receptors and undergo cell type-specific transcriptomic reprogramming in disease. The advance of single-cell genomics has provided a powerful tool for unraveling the complexity of liver cells in health and disease with unprecedented resolution. In this review, we discuss insights gained from the recent sin...
Source
#1Steven Balog (SC: University of Southern California)H-Index: 3
#2Yuchang Li (SC: University of Southern California)H-Index: 7
Last. Kinji Asahina (SC: University of Southern California)H-Index: 30
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: Glisson's capsule is the connective tissue present in the portal triad as well as beneath the liver surface. Little is known about how Glisson's capsule changes its structure in capsular fibrosis (CF), which is characterized by fibrogenesis beneath the liver surface. In this study, we found that the human liver surface exhibits multilayered capsular fibroblasts and that the bile duct is present beneath the mesothelium, whereas capsular fibroblasts are scarce and no bile ducts are present benea...
Source
#1Ross Dobie (Edin.: University of Edinburgh)H-Index: 12
#2John R Wilson-Kanamori (Edin.: University of Edinburgh)H-Index: 6
Last. Neil C. Henderson (Edin.: University of Edinburgh)H-Index: 36
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Summary 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 part...
Source
#1Mousumi Khatun (SLU: Saint Louis University)H-Index: 4
#2Ratna B. Ray (SLU: Saint Louis University)H-Index: 3
Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, inc...
Source
#1Prakash Ramachandran (Edin.: University of Edinburgh)H-Index: 19
#2Ross Dobie (Edin.: University of Edinburgh)H-Index: 12
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Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic hum...
Source
#1Takahiro Nishio (UCSD: University of California, San Diego)H-Index: 18
#2Ronglin Hu (UCSD: University of California, San Diego)H-Index: 3
Last. Tatiana Kisseleva (UCSD: University of California, San Diego)H-Index: 50
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Abstract null null Aim null Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury. null null null Materials & methods null...
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Studies of the identity and pathophysiology of fibrogenic hepatic stellate cells (HSCs) have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single cell RNA sequencing of non-parenchymal cells from mouse liver, we identified Tcf21 as a unique marker that restricted its expression to quiescent HSCs. Tracing Tcf21+ cells by Tcf21-CreER targeted ~10% of all HSCs, most of which located at periportal and pericentral zones. Thes...
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Background & Aims: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolut...
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Heterogeneity among hepatic stellate cells (HSCs), widely acknowledged as the 'stars' of hepatic fibrosis, has been hinted at for decades based on immunohistochemical methods. Now, more refined approaches, epitomized by the studies of Rosenthal et al. in this issue of Hepatology, have amplified this concept. Earlier investigators noted striking variability across the hepatic lobule in hallmark features of HSCs including vitamin A storage and dendritic arborization -- indications that not every H...
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