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:10.2139/ssrn.3351829

Cited by 7 publications

(15 citation statements)

References 52 publications

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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: Resultsmentioning

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: Resultsmentioning

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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“…In the mouse CNS, Cndp2 (as well as transporters Pht1/2, Pept2) are mainly expressed by microglia and astrocytes [56], which may explain their general increase during EAE. Human and mouse RNA sequencing studies indicate that CARNS1 is almost exclusively expressed in mature oligodendrocytes [56][57][58][59][60][61][62][63]. Oligodendrocyte dysfunction, death and demyelination may therefore underlie the reduction in Carns1 expression seen in acute EAE [64].…”

Section: Discussionmentioning

confidence: 99%

Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation

Spaas

Franssen

Keytsman

et al. 2021

J Neuroinflammation

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Background Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. Methods The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). Results Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. Conclusions Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.

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“…On the other hand, two recent studies using quantitative proteomics on homogenates of isolated microvessels and single-cell RNA sequencing (RNA-seq) reported lower levels of transporter proteins and transcripts in GBM compared to normal brain tissue. 34,35 Proteomics is more quantitative, but it lacks information on spatial distribution and is very much dependent on the vessel content in the homogenate. Moreover, the surgical specimens in both studies are likely to contain more material from the central part of the tumor than from the invasive areas.…”

Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost

Gooijer

Kemper

Buil

et al. 2021

Cell Reports Medicine

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The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, fluorescent dyes, and autoradiography and determine the distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATPbinding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.

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

Cited by 7 publications

References 52 publications

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

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

Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation

ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost

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