GATA4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells

Olsavszky, Victor; Ulbrich, Friederike; Singh, Sandhya; Diett, Miriam; Sticht, Carsten; Schmid, Christian David; Zierow, Johanna; Wohlfeil, Sebastian A.; Schledzewski, Kai; Dooley, Steven; Gaitantzi, H; Breitkopf‐Heinlein, Katja; Géraud, Cyrill; Goerdt, Sergij; Koch, Philipp-Sebastian

doi:10.1016/j.gene.2017.06.051

Cited by 20 publications

(8 citation statements)

References 31 publications

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“…Notably, gut microbiome-mediated primary-to-secondary bile acid conversion induces secretion of Cxcl16 by LSEC regulating NK-cell accumulation (20). Surprisingly, angiocrine signaling pathways such as Wnt signaling (21)(22)(23)(24)(25), Hgf signaling (26), and Bmp2 signaling (27,28), described by us and others to govern liver development, liver function, and liver regeneration, have not been checked for their role in liver metastasis. In addition, known superordinate molecular regulators of angiocrine signaling in the liver such as Gata4 (29) have also not been scrutinized for their involvement in hepatic metastasis.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

et al. 2019

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The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cre tg/wt mice were crossed to Rosa26 N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICD OE-HEC). In NICD OE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of Wls HEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICD OE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner. Significance: Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell-and context-specific fashion.

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Section: Introductionmentioning

confidence: 99%

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

et al. 2019

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“…We were also interested in whether the BMP pathway could contribute to innate immune defence against viral infection. A recent report indirectly suggested that BMP2 may drive a transcriptome that included elements reminiscent of virus-induced and interferon associated responses 10 . However the functional significance of these effects for viral replication and antiviral immunity remained unclear.…”

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confidence: 99%

Antiviral activity of bone morphogenetic proteins and activins

et al. 2018

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Understanding the control of viral infections is of broad importance. Chronic HCV infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic BMP/SMAD signaling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, likely via TNF-mediated downregulation of the BMP co-receptor HJV. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted outcome of infection, suggesting BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of Type I IFN signaling, including upregulating IRFs and downregulating an inhibitor of IFN signaling, USP18. Moreover, in BMP stimulated cells, SMAD1 occupied loci across the genome similar to those bound by IRF1 in IFN stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related Activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and Activin A suppressed growth of HBV in cell culture, and Activin A inhibited ZIKV replication alone and in combination with IFN. The data establish an unappreciated important role for the BMPs and Activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

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“…These genetic experiments validated GATA4 as a molecular master regulator of hepatic angiodiversity, controlling LSEC specification and fetal liver development by establishing a hepatic niche required for proper HSPC [36]. Corresponding cellular experiments showed that GATA4 prevents, in cooperation with the transcriptional co-regulator LMO3, the autocrine induction of a pro-inflammatory phenotype while maintaining angiocrine signaling through the GATA4-downstream target BMP2 [59]. Interestingly, ectopic GATA4 overexpression in HUVEC resulted in the strong suppression of a continuous EC gene signature with a less stringent upregulation of LSEC-associated genes [36].…”

Section: Transcription Factors Regulating Lsec Differentiationmentioning

confidence: 77%

Angiodiversity and organotypic functions of sinusoidal endothelial cells

et al. 2021

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Abstract‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.

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GATA4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells

Cited by 20 publications

References 31 publications

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

Antiviral activity of bone morphogenetic proteins and activins

Angiodiversity and organotypic functions of sinusoidal endothelial cells

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