Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis

Yang, Yoon Mee; Noureddin, Mazen; Liu, Cheng; Ohashi, Kenichi; Kim, So Yeon; Ramnath, Divya; Powell, Elizabeth E.; Sweet, Matthew J.; Roh, Yoon Seok; Hsin, I-Fang; Deng, Nan; Liu, Zhenqiu; Liang, Jiurong; Mena, Edward; Shouhed, Daniel; Schwabe, Robert F.; Jiang, Dianhua; Lu, Shelly C.; Noble, Paul W.; Seki, Ekihiro

doi:10.1126/scitranslmed.aat9284

Cited by 113 publications

(132 citation statements)

References 52 publications

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“…Jagged-1 expressed on liver macrophages and HSCs could interact with Notch1 on HSCs, promoting Notch1-mediated HSC activation and fibrosis. 57 These observations support that the bidirectional regulation between macrophages and HSCs is the key mechanism of fibrosis progression.…”

Section: Crosstalk Of Hscs and Macrophages Is Crucial For Liver Fibromentioning

confidence: 54%

“…Activated HSCs overexpress HAS2 that synthesizes HA, and then the overproduced HA promotes HSC activation and fibrosis through CD44/Notch signaling. 57 ECM stiffness also contributes to HSC activation. Compositional changes and crosslinking of collagen fibers by lysyl oxidaselike enzyme (LOXL) contribute to the increased stiffness of fibrosis, which activates HSCs through mechanosensing signaling, including the YAP-activating pathway.…”

Section: The Role Of Hepatic Stellate Cells In Liver Fibrosis and Canmentioning

confidence: 99%

“…136 In addition, the nonprotein glycosaminoglycan HA also is increasingly deposited in fibrotic livers. 57 Among these ECM components, we recently reported that HA activates HSCs through CD44 and TLR4 in the chronically injured liver. 57 HA can also promote HCC progression through CD44.…”

Section: Ecm Remodeling Plays a Role In Fibrosis And Hccmentioning

confidence: 99%

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Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

2020

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Chronic liver injury due to viral hepatitis, alcohol abuse, and metabolic disorders is a worldwide health concern. Insufficient treatment of chronic liver injury leads to fibrosis, causing liver dysfunction and carcinogenesis. Most cases of hepatocellular carcinoma (HCC) develop in the fibrotic liver. Pathological features of liver fibrosis include extracellular matrix (ECM) accumulation, mesenchymal cell activation, immune deregulation, and angiogenesis, all of which contribute to the precancerous environment, supporting tumor development. Among liver cells, hepatic stellate cells (HSCs) and macrophages play critical roles in fibrosis and HCC. These two cell types interplay and remodel the ECM and immune microenvironment in the fibrotic liver. Once HCC develops, HCC-derived factors influence HSCs and macrophages to switch to protumorigenic cell populations, cancer-associated fibroblasts and tumor-associated macrophages, respectively. This review aims to summarize currently available data on the roles of HSCs and macrophages in liver fibrosis and HCC, with a focus on their interaction.

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Section: Crosstalk Of Hscs and Macrophages Is Crucial For Liver Fibromentioning

confidence: 54%

Section: The Role Of Hepatic Stellate Cells In Liver Fibrosis and Canmentioning

confidence: 99%

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Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

2020

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“…A recent extensive study demonstrated that conditional knockout of has2 HSCs reduced liver fibrosis in mice [31]. It also shows that HAS2 was upregulated by transforming growth factor-β through Wilms tumor 1 to promote transdifferentiation of HSCs towards myofibroblasts.…”

Section: Discussionmentioning

confidence: 97%

4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

Andreichenko

Tsitrina

Фокин

et al. 2019

IJMS

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4-methylumbelliferone (4MU) is an inhibitor of hyaluronan deposition and an active substance of hymecromone, a choleretic and antispasmodic drug. 4MU reported to be anti-fibrotic in mouse models; however, precise mechanism of action still requires further investigation. Here we describe the cellular and molecular mechanisms of 4MU action on CCl4-induced liver fibrosis in mice using NGS transcriptome, Q-PCR and immunohistochemical analysis. Collagen and hyaluronan deposition were prevented by 4MU. The CCl4 stimulated expression of Col1a and αSMA were reduced, while the expression of the ECM catabolic gene Hyal1 was increased in the presence of 4MU. Bioinformatic analysis identified an activation of TGF-beta and Wnt/beta-catenin signaling pathways, and inhibition of the genes associated with lipid metabolism by CCL4 treatment, while 4MU restored key markers of these pathways to the control level. Immunohistochemical analysis reveals the suppression of hepatic stellate cells (HSCs) transdifferentiation to myofibroblasts by 4MU treatment. The drug affected the localization of HSCs and macrophages in the sites of fibrogenesis. CCl4 treatment induced the expression of FSTL1, which was downregulated by 4MU. Our results support the hypothesis that 4MU alleviates CCl4-induced liver fibrosis by reducing hyaluronan deposition and downregulating FSTL1 expression, accompanied by the suppression of HSC trans-differentiation and altered macrophage localization.

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“…Hepatic stellate cells are a possible source of hyaluronan that could possibly be activated in this specific context. 83 Similarly, liver endothelial cells could actively participate in hyaluronan remodelling and production. 84 Finally, genetic impairment of platelets' ability to release αgranules (in Nbeal2 -/mice) resulted in amelioration of liver damage and inflammation, whereas simple inhibition of platelet aggregation did not reveal any beneficial effect.…”

Section: Platelets In Alcohol-related and Non-alcoholic Steatohepatitismentioning

confidence: 99%

Platelets in chronic liver disease, from bench to bedside

et al. 2019

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In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shiftedplatelets are now seen as alert "sentinels" of the immune compartment, rather than passive bystanders. Herein, we review well-established and newly discovered features of platelets that define their natural role in maintaining blood haemostasis, but also their functional relationship with other cells of the immune system. We focus on recent studies underlining functional involvement of platelets in chronic liver diseases and cancer, as well as the effects of anti-platelet therapy in these contexts. Finally, we illustrate the potential of platelets as possible diagnostic and therapeutic tools in liver disease based on recently developed methodologies.

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Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis

Cited by 113 publications

References 52 publications

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

Platelets in chronic liver disease, from bench to bedside

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