Biology subjects

Monnier, P.

Publications and source records attributed to Monnier, P..

6 recordsLinked to original sources

bioRxiv2022

Suppression of Betacellulin expression is a key mechanism for omega-3 fatty acid mediated attenuation of nonalcoholic steatohepatitis

Clinical and preclinical studies have established that supplementing diets with {omega}3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH). Herein, we used multi-omic network analysis to unveil novel mechanistic targets of {omega}3 PUFA effects in a preclinical mouse model of western diet induced NASH. After identifying critical molecular processes responsible for the effects of {omega}3 PUFA, we next performed meta-analysis of human liver cancer transcriptomes and uncovered betacellulin as a key EGFR-binding protein that was induced in liver cancer and downregulated by {omega}3 PUFAs in animals with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, stimulating transforming growth factor-{beta}2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti-inflammatory and antifibrotic effects of {omega}3 PUFA during NASH. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/510635v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b8ebe7org.highwire.dtl.DTLVardef@879e8dorg.highwire.dtl.DTLVardef@1ba56f3org.highwire.dtl.DTLVardef@a26c67_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIMulti-omic network analysis points to mitochondrial cardiolipin precursors as candidate key lipids whereby {omega}3 fatty acids restore mitochondrial functioning. C_LIO_LIMulti-omic network analysis suggests betacellulin (BTC) as one of the key mediators of NASH suppressed by {omega}3 polyunsaturated fatty acids. C_LIO_LIReduction of liver fibrosis by omega-3 fatty acids (especially by docosahexaenoic acid, DHA) is accomplished by simultaneous inhibition of betacellulin and TLR agonists. C_LIO_LIBTC promotes collagen production and induces TGFB2 in hepatic stellate cells. C_LIO_LIBTC together with TLR2/4 agonists stimulate expression of integrins in macrophages. C_LIO_LIDHA suppresses BTC-EGFR pathway in NASH animal model potentially preventing progression to hepatocellular carcinoma. C_LI

systems biology↗

bioRxiv2021

Molecular atlas of the human brain vasculature at the single-cell level

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains poorly understood. Here, we performed single-cell RNA sequencing of 599,215 freshly isolated endothelial, perivascular and other tissue-derived cells from 47 fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We uncover extensive molecular heterogeneity of healthy fetal and adult human brains and across eight vascular-dependent CNS pathologies including brain tumors and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict numerous endothelial-to-perivascular cell ligand-receptor crosstalk including immune-related and angiogenic pathways, thereby unraveling a central role for the endothelium within brain neurovascular unit signaling networks. Our single-cell brain atlas provides insight into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

neuroscience↗

bioRxiv2020

Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain

The formation of new blood vessels and the establishment of vascular networks are crucial during brain development, in the adult healthy brain, as well as in various diseases of the central nervous system (CNS). Here, we describe a method that enables hierarchical imaging and computational analysis of vascular networks in postnatal- and adult mouse brains. Resin-based vascular corrosion casting, scanning electron microscopy, synchrotron radiation and desktop {micro}CT imaging, and computational network analysis are used. Combining these methods enables detailed visualization and quantification of the three-dimensional (3D) brain vasculature. Network features such as vascular volume fraction, branch point density, vessel diameter, - length, -tortuosity, and -directionality as well as extravascular distance can be obtained at any developmental stage from the early postnatal to the adult brain. Our method allows characterizing brain vascular networks separately for capillaries and non-capillaries. The entire protocol, from mouse perfusion to vessel network analysis, takes approximately 10 days. Online summaryThis protocol uses vascular corrosion casting, hierarchical synchrotron radiation {micro}CT imaging, and computational image analysis to assess the three-dimensional vascular network architecture.

neuroscience↗

bioRxiv2020

Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

Glioblastoma (GBM) is amongst the deadliest human cancers and is characterized by high levels of vascularisation. Angiogenesis is highly dynamic during brain development and almost quiescent in the adult brain, but is reactivated in vascular-dependent CNS pathologies such as brain tumors. Nucleolin (NCL) is a known regulator of cell proliferation and angiogenesis, but its roles on physiological and pathological brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit (NVU) in human fetal brains and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial- and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression in tumor- and blood vessel cells correlated with glioma malignancy in vivo. In culture, siRNA-mediated NCL knockdown reduced human umbilical vein endothelial cell (HUVEC) sprouting angiogenesis, proliferation and filopodia extension, and reduced glucose metabolism. Mechanistically, RNA sequencing of Nucleolin knockdown in HUVECs revealed a putative p53-TIGAR-HK2 regulation of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that positively regulates sprouting angiogenesis and endothelial metabolism. Our findings have important implications in therapeutic targeting of glioma.

neuroscience↗

bioRxiv2020

The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors

A large number of hospitalized COVID-19 patients show neurological symptoms such as ischemic- and hemorrhagic stroke as well as encephalitis, and SARS-CoV-2 can directly infect endothelial cells leading to endotheliitis across multiple vascular beds. These findings suggest an involvement of the brain- and peripheral vasculature in COVID-19, but the underlying molecular mechanisms remain obscure. To understand the potential mechanisms underlying SARS-CoV-2 tropism for brain vasculature, we constructed a molecular atlas of the expression patterns of SARS-CoV-2 viral entry-associated genes (receptors and proteases) and SARS-CoV-2 interaction partners in human (and mouse) adult and fetal brain as well as in multiple non-CNS tissues in single-cell RNA-sequencing data across various datasets. We observed a distinct expression pattern of the cathepsins B (CTSB) and -L (CTSL) - which are able to substitute for the ACE2 co-receptor TMPRSS2 - in the human vasculature with CTSB being mainly expressed in the brain vasculature and CTSL predominantly in the peripheral vasculature, and these observations were confirmed at the protein level in the Human Protein Atlas and using immunofluorescence stainings. This expression pattern of SARS-CoV-2 viral-entry associated proteases and SARS-CoV-2 interaction partners was also present in endothelial cells and microglia in the fetal brain, suggesting a developmentally established SARS-CoV-2 entry machinery in the human vasculature. At both the adult and fetal stages, we detected a distinct pattern of SARS-CoV-2 entry associated genes transcripts in brain vascular endothelial cells and microglia, providing a potential explanation for an inflammatory response in the brain endothelium upon SARS-CoV-2 infection. Moreover, CTSB was co-expressed in adult and fetal brain endothelial cells with genes and pathways involved in innate immunity and inflammation, angiogenesis, blood-brain-barrier permeability, vascular metabolism, and coagulation, providing a potential explanation for the role of brain endothelial cells in clinically observed (neuro)vascular symptoms in COVID-19 patients. Our study serves as a publicly available single-cell atlas of SARS-CoV-2 related entry factors and interaction partners in human and mouse brain endothelial- and perivascular cells, which can be employed for future studies in clinical samples of COVID-19 patients.

neuroscience↗

bioRxiv2020

Open syntaxin overcomes synaptic transmission defects in diverse C. elegans exocytosis mutants

Assembly of SNARE complexes that mediate neurotransmitter release requires opening of a closed conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibited enhanced spontaneous and evoked exocytosis compared to wild-type animals. Unexpectedly, the open syntaxin KI partially suppressed exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit, and unc-31/CAPS in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravated the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.

neuroscience↗