A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes

Dusart, Philip; Hallström, Björn M.; Renné, Thomas; Odeberg, Jacob; Uhlén, Mathias; Butler, Lynn M.

doi:10.1016/j.celrep.2019.09.088

Cited by 25 publications

(27 citation statements)

References 96 publications

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“…Previous bulk analysis–based transcriptomic studies have revealed limited insights into the characteristics of ECs in normal brain and GBM ( 7 , 8 ). In bulk RNA analysis, cellular heterogeneity gets lost in the average of gene expression from all cells, and contaminations from other cell types cannot be deduced, together posing severe limitations to interpretations and the possibilities for correctly assigning EC-specific changes and their heterogeneity within the EC population.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular alteration of ECs has been observed in patients and animal models of many brain diseases, including stroke, multiple sclerosis, traumatic brain injury and GBM (5,6). By analysis of bulk mRNA isolated from brain ECs, we and others have shown that the abnormal vessels in GBM are associated with a distinct gene signature (7)(8)(9). However, the more precise characteristics of endothelial gene expression in GBM, including possible heterogeneity that cannot be resolved using bulk methods, is still poorly understood.…”

Section: Introductionmentioning

confidence: 96%

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Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Xie¹,

He²,

Lugano³

et al. 2021

JCI Insight

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Glioblastoma is the most aggressive type of brain tumor with poor therapeutic response and prognosis. Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (EC). Tumor vessels in GBM are abnormal and more permeable, but the heterogeneity of BBB breakdown in different parts of the tumor vasculature and at the tumor's invasive front is largely unknown. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Xie¹,

He²,

Lugano³

et al. 2021

JCI Insight

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“…On the other hand, an up-regulation of 3884 out of 13,485 genes is seen from P0D0 to P0D7 (≥1.5-fold, p ≤ 0.05), most probably representing endothelial-specific genes, and thus reflecting the in vitro selection of the endothelial cell population. The degree of purity of P0D0 and in vitro-selected P0D7 and P1D7 samples was assessed through probing the transcriptome data for the expression of 5 acknowledged cell type specific genes [18][19][20][21] for astrocytes (BMPR1B, GFAP, ALDH1L1, SOX9, AQP4), neurons (TMEM130, RELN, STMN2, SYT1, SYN1), oligodendrocytes (MAG, PLP1, MOG, MOBP, MBP), and microglia (AIF1, C1QA, C1QB, CX3CR1, TNF), and 10 genes for endothelial cells (SLC2A1/GLUT1, EPAS1, ITM2A, CLDN5, BSG, CD34, VWF, PECAM1, CDH5, ESAM) (Figure 1(B2)). All non-endothelial cell markers see their expression being switched-off in P0D7 and P1D7 cell populations, while the expression of the selected endothelial genes is either maintained or even increased in both the P0D7 and P1D7 cell populations, in comparison to P0D0 (Figure 1(C1)).…”

Section: Transcriptional Profiling Of Brain Microvasculaturementioning

confidence: 99%

Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

Chaves

Cegarra

et al. 2020

Pharmaceutics

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The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were investigated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.

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Section: Identification Of Endothelial-enriched Genes In Gbmmentioning

confidence: 99%

“…To explore the effect of vascular ECs on contrast enhancement in MRI, we first identified EC-enriched genes by a systematic approach through performing the correlation analysis of the expression profiles of all gene transcripts to the known EC marker gene as previously described (20,21). A high average correlation coefficient with those EC marker genes indicates the enrichment of the genes in EC (20,21). We analyzed transcriptome data from 128 GBM cases with available MRI records in TCGA (Table S1) to produce the average correlation values between EC marker genes (CDH5, CLDN5, VWF) and the other >20,000 protein encoding genes, yielding 343 EC-enriched genes manifesting correlation coefficient >0.3 (Figures 1A, B and Table S2).…”

Section: Identification Of Endothelial-enriched Genes In Gbmmentioning

confidence: 99%

Uncovering a Distinct Gene Signature in Endothelial Cells Associated With Contrast Enhancement in Glioblastoma

et al. 2021

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PurposeGlioblastoma (GBM) is the most aggressive and lethal type of brain tumors. Magnetic resonance imaging (MRI) has been commonly used for GBM diagnosis. Contrast enhancement (CE) on T1-weighted sequences are presented in nearly all GBM as a result of high vascular permeability in glioblastomas. Although several radiomics studies indicated that CE is associated with distinct molecular signatures in tumors, the effects of vascular endothelial cells, the key component of blood brain barrier (BBB) controlling vascular permeability, on CE have not been thoroughly analyzed.MethodsEndothelial cell enriched genes have been identified using transcriptome data from 128 patients by a systematic method based on correlation analysis. Distinct endothelial cell enriched genes associated with CE were identified by analyzing difference of correlation score between CE-high and CE–low GBM cases. Immunohistochemical staining was performed on in-house patient cohort to validate the selected genes associated with CE. Moreover, a survival analysis was conducted to uncover the relation between CE and patient survival.ResultsWe illustrated that CE is associated with distinct vascular molecular imprints characterized by up-regulation of pro-inflammatory genes and deregulation of BBB related genes. Among them, PLVAP is up-regulated, whereas TJP1 and ABCG2 are down-regulated in the vasculature of GBM with high CE. In addition, we found that the high CE is associated with poor prognosis and GBM mesenchymal subtype.ConclusionWe provide an additional insight to reveal the molecular trait for CE in MRI images with special focus on vascular endothelial cells, linking CE with BBB disruption in the molecular level. This study provides a potential new direction that may be applied for the treatment optimization based on MRI features.

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A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes

Cited by 25 publications

References 96 publications

Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

Uncovering a Distinct Gene Signature in Endothelial Cells Associated With Contrast Enhancement in Glioblastoma

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