scholarly journals Human Blood Vessel Organoids Penetrate Human Cerebral Organoids and Form a Vessel-Like System

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2036
Author(s):  
Yujin Ahn ◽  
Ju-Hyun An ◽  
Hae-Jun Yang ◽  
Dong Gil Lee ◽  
Jieun Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Cell Types ◽  
Brain Barrier ◽  
Vascular Cells ◽  
Blood Brain ◽  
Vessel Networks

Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood–brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31+ endothelial tubes coated with SMA+ or PDGFR+ mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days.

scholarly journals Culture-Induced Changes in Blood—Brain Barrier Transcriptome: Implications for Amino-Acid Transporters in vivo

2009 ◽  
Vol 29 (9) ◽  
pp. 1491-1502 ◽  
Author(s):  
Ruth Lyck ◽  
Nadine Ruderisch ◽  
Anton G Moll ◽  
Oliver Steiner ◽  
Clemens D Cohen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Amino Acid Transporters ◽  
Mrna Levels ◽  
Blood Brain ◽  
Barrier Formation ◽  
Platelet Endothelial Cell Adhesion ◽  
Induced Changes

Tight homeostatic control of brain amino acids (AA) depends on transport by solute carrier family proteins expressed by the blood—brain barrier (BBB) microvascular endothelial cells (BMEC). To characterize the mouse BMEC transcriptome and probe culture-induced changes, microarray analyses of platelet endothelial cell adhesion molecule-1-positive (PECAM1+) endothelial cells (ppMBMECs) were compared with primary MBMECs (pMBMEC) cultured in the presence or absence of glial cells and with b.End5 endothelioma cell line. Selected cell marker and AA transporter mRNA levels were further verified by reverse transcription real-time PCR. Regardless of glial coculture, expression of a large subset of genes was strongly altered by a brief culture step. This is consistent with the known dependence of BMECs on in vivo interactions to maintain physiologic functions, for example, tight barrier formation, and their consequent dedifferentiation in culture. Seven ( 4F2hc, Lat1, Taut, Snat3, Snat5, Xpct, and Cat1) of nine AA transporter mRNAs highly expressed in freshly isolated ppMBMECs were strongly downregulated for all cultures and two ( Snat2 and Eaat3) were variably regulated. In contrast, five AA transporter mRNAs with low expression in ppMBMECs, including y+ Lat2, xCT, and Snat1, were upregulated by culture. We hypothesized that the AA transporters highly expressed in ppMBMECs and downregulated in culture have a major in vivo function for BBB transendothelial transport.

scholarly journals Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

2020 ◽  
Vol 21 (2) ◽  
pp. 591 ◽  
Author(s):  
Wolfgang Löscher ◽  
Alon Friedman
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Defense Mechanism ◽  
Extracellular Fluid ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Transport Systems ◽  
Blood Brain ◽  
The Brain

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

scholarly journals 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes

Biomaterials ◽  
2018 ◽  
Vol 180 ◽  
pp. 117-129 ◽  
Author(s):  
Marco Campisi ◽  
Yoojin Shin ◽  
Tatsuya Osaki ◽  
Cynthia Hajal ◽  
Valeria Chiono ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Brain Barrier ◽  
Self Organized ◽  
Blood Brain

scholarly journals Human pluripotent stem cell–derived brain pericyte–like cells induce blood-brain barrier properties

2019 ◽  
Vol 5 (3) ◽  
pp. eaau7375 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Barrier Properties ◽  
Cell Types ◽  
Brain Barrier ◽  
Human Model ◽  
Blood Brain ◽  
Brain Pericytes

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte–like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte–like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte–like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte–like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

scholarly journals Cerebromicrovascular endothelial cells are resistant to l-glutamate

2008 ◽  
Vol 295 (4) ◽  
pp. R1099-R1108 ◽  
Author(s):  
Ferenc Domoki ◽  
Béla Kis ◽  
Tamás Gáspár ◽  
Ferenc Bari ◽  
David W. Busija
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Primary Cultures ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Cranial Window ◽  
Blood Brain ◽  
Microvascular Cells

Cerebral microvascular endothelial cells (CMVECs) have recently been implicated as targets of excitotoxic injury by l-glutamate (l-glut) or N-methyl-d-aspartate (NMDA) in vitro. However, high levels of l-glut do not compromise the function of the blood-brain barrier in vivo. We sought to determine whether primary cultures of rat and piglet CMVECs or cerebral microvascular pericytes (CMVPCs) are indeed sensitive to l-glut or NMDA. Viability was unaffected by 8-h exposure to 1–10 mM l-glut or NMDA in CMVECs or CMVPCs isolated from both species. Furthermore, neither 1 mM l-glut nor NMDA augmented cell death induced by 12-h oxygen-glucose deprivation in rat CMVECs or by 8-h medium withdrawal in CMVPCs. Additionally, transendothelial electrical resistance of rat CMVEC-astrocyte cocultures or piglet CMVEC cultures were not compromised by up to 24-h exposure to 1 mM l-glut or NMDA. The Ca2+ ionophore calcimycin (5 μM), but not l-glut (1 mM), increased intracellular Ca2+ levels in rat CMVECs and CMVPCs assessed with fluo-4 AM fluorescence and confocal microscopy. CMVEC-dependent pial arteriolar vasodilation to hypercapnia and bradykinin was unaffected by intracarotid infusion of l-glut in anesthetized piglets by closed cranial window/intravital microscopy. We conclude that cerebral microvascular cells are insensitive and resistant to glutamatergic stimuli in accordance with their in vivo role as regulators of potentially neurotoxic amino acids across the blood-brain barrier.

scholarly journals A three-dimensional model of the human blood-brain barrier to analyse the transport of nanoparticles and astrocyte/endothelial interactions

F1000Research ◽  
2016 ◽  
Vol 4 ◽  
pp. 1279 ◽  
Author(s):  
Peddagangannagari Sreekanthreddy ◽  
Radka Gromnicova ◽  
Heather Davies ◽  
James Phillips ◽  
Ignacio A. Romero ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Human Blood ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Cell Types ◽  
Brain Barrier ◽  
Two Dimensional ◽  
Three Dimensional Model ◽  
Blood Brain

The aim of this study was to develop a three-dimensional (3D) model of the human blood-brain barrier in vitro, which mimics the cellular architecture of the CNS and could be used to analyse the delivery of nanoparticles to cells of the CNS. The model includes human astrocytes set in a collagen gel, which is overlaid by a monolayer of human brain endothelium (hCMEC/D3 cell line). The model was characterised by transmission electron microscopy (TEM), immunofluorescence microscopy and flow cytometry. A collagenase digestion method could recover the two cell types separately at 92-96% purity.  Astrocytes grown in the gel matrix do not divide and they have reduced expression of aquaporin-4 and the endothelin receptor, type B compared to two-dimensional cultures, but maintain their expression of glial fibrillary acidic protein. The effects of conditioned media from these astrocytes on the barrier phenotype of the endothelium was compared with media from astrocytes grown conventionally on a two-dimensional (2D) substratum. Both induce the expression of tight junction proteins zonula occludens-1 and claudin-5 in hCMEC/D3 cells, but there was no difference between the induced expression levels by the two media. The model has been used to assess the transport of glucose-coated 4nm gold nanoparticles and for leukocyte migration. TEM was used to trace and quantitate the movement of the nanoparticles across the endothelium and into the astrocytes. This blood-brain barrier model is very suitable for assessing delivery of nanoparticles and larger biomolecules to cells of the CNS, following transport across the endothelium.

scholarly journals Inflammation Modulates RLIP76/RALBP1 Electrophile-Glutathione Conjugate Transporter and Housekeeping Genes in Human Blood-Brain Barrier Endothelial Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0139101 ◽  
Author(s):  
Barbara Bennani-Baiti ◽  
Stefan Toegel ◽  
Helmut Viernstein ◽  
Ernst Urban ◽  
Christian R. Noe ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Housekeeping Genes ◽  
Brain Barrier ◽  
Glutathione Conjugate ◽  
Blood Brain

scholarly journals Blood-Brain Barrier Dysfunction in the Detrimental Brain Function

2021 ◽  
Author(s):  
Alejandro Gonzalez-Candia ◽  
Nicole K. Rogers ◽  
Rodrigo L. Castillo
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Function ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Microvascular Endothelium ◽  
Blood Brain ◽  
And Function

The blood circulation interface and the neural tissue feature unique characteristics encompassed by the term blood -brain barrier (BBB). The barrier’s primary functions are maintenance of brain homeostasis, selective transport, and protection, all of them determined by its specialized multicellular structure. The BBB primarily exists at the level of the brain microvascular endothelium; however, endothelial cells are not intrinsically capable of forming a barrier. Indeed, the development of barrier characteristics in cerebral endothelial cells requires coordinated cell–cell interactions and signaling from glial cells (i.e., astrocytes, microglia), pericytes, neurons, and extracellular matrix. Such an intricate relationship implies the existence of a neurovascular unit (NVU). The NVU concept emphasizes that the dynamic BBB response to stressors requires coordinated interactions between various central nervous system (CNS) cell types and structures. Every cell type makes an indispensable contribution to the BBBs integrity, and any cell’s failure or dysfunction might result in the barrier breakdown, with dramatic consequences, such as neuroinflammation and neurodegeneration. This chapter will focus on the structure and function of the BBB and discuss how BBB breakdown causes detrimental brain function.

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