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      The hCMEC/D3 cell line as a model of the human blood brain barrier

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          Abstract

          Since the first attempts in the 1970s to isolate cerebral microvessel endothelial cells (CECs) in order to model the blood–brain barrier (BBB) in vitro, the need for a human BBB model that closely mimics the in vivo phenotype and is reproducible and easy to grow, has been widely recognized by cerebrovascular researchers in both academia and industry. While primary human CECs would ideally be the model of choice, the paucity of available fresh human cerebral tissue makes wide-scale studies impractical. The brain microvascular endothelial cell line hCMEC/D3 represents one such model of the human BBB that can be easily grown and is amenable to cellular and molecular studies on pathological and drug transport mechanisms with relevance to the central nervous system (CNS). Indeed, since the development of this cell line in 2005 over 100 studies on different aspects of cerebral endothelial biology and pharmacology have been published. Here we review the suitability of this cell line as a human BBB model for pathogenic and drug transport studies and we critically consider its advantages and limitations.

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          Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study.

          A Butt, H. C. Jones, N J Abbott (1990)
          1. Ion permeability of the blood-brain barrier was studied by in situ measurement of transendothelial electrical resistance in anaesthetized rats aged between 17 days gestation and 33 days after birth, and by electron microscopic examination of lanthanum permeability in fetal and neonatal rats aged up to 10 days old. 2. The blood-brain barrier in 17- to 20-day fetuses had a resistance of 310 omega cm2 but was impermeable to lanthanum, and therefore had properties intermediate between leaky and tight epithelia. 3. From 21 days gestation, the resistance was 1128 omega cm2, indicating a tight blood-brain barrier and low ion permeability. There was little further change in barrier resistance after birth, and in 28- to 33-day rats, when the brain barrier systems are mature in other ways, vessels had a mean resistance of 1462 omega cm2. 4. In the tight blood-brain barrier, arterial vessels had a significantly higher resistance than venous vessels, 1490 and 918 omega cm2 respectively. In vessels less than 50 microns diameter and within the normal 60 min experimental period, there was no significant variation in vessel resistance. 5. Hyperosmotic shock caused a rapid decay in resistance (maximal within 5 min), and after disruption of the blood-brain barrier, vessel resistance was 100-300 omega cm2 in both arterial and venous vessels, and the effect was reversible. After the application of metabolic poisons (NaCN plus iodoacetate) and low temperature there was a similarly low electrical resistance. 6. It is concluded that the increase in electrical resistance at birth indicates a decrease in paracellular ion permeability at the blood-brain barrier and is required for effective brain interstitial fluid ion regulation.
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            Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models.

            Kathryn Hatherell, P Olivier Couraud, Babette B Weksler … (2011)
            In vitro models of the blood-brain barrier (B-BB) generally utilise murine or porcine brain endothelium and rat astrocytes which are commonly grown in foetal calf serum supplemented conditions which modulate cell growth rates. Consequently, results gained from these experimental models can be difficult to extrapolate to the human in vivo situation since they are not of human origin. The proposed in vitro Transwell model of the B-BB is a multi-culture human cell system. It requires reconstruction of the human derived B-BB components in vitro (cerebral microvascular endothelial cells, astrocytes, and brain vascular pericytes) in a three-dimensional (3D) configuration based on Transwell filters. Different cell permutations (mono-, co-, and tri-cultivation) were investigated to find the most effective model in terms of tight junction resistance of the human cerebral microvascular endothelial cells. The B-BB model permutations comprised of human astrocytes (CC-2565 and SC-1810), human brain vascular pericytes (HBVP), and human cerebral microvascular endothelial cells (hCMEC/D3), under human serum supplementation. The models were assessed by trans-endothelial electrical resistance (TEER) measurements using an epithelial voltohmmeter, to validate the tight junction formation between hCMEC/D3 cells. Mono-, co-, and tri-cultivation Transwell models constructed with human brain-derived cells under human serum supplementation demonstrated that co-cultivation of astrocytes with endothelial cells produced the most successful model, as determined by TEER. Pericytes on the other hand improved tight junction formation when co-cultured with endothelial cells but did not improve the model to such an extent when grown in tri-cultivation with astrocytes. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Differential effects of hydrocortisone and TNFalpha on tight junction proteins in an in vitro model of the human blood-brain barrier.

              Malgorzata Burek, Babette B Weksler, P Olivier Couraud … (2008)
              Homeostasis of the central nervous system (CNS) microenvironment is maintained by the blood-brain barrier (BBB) which regulates the transport of molecules from blood into brain and back. Many disorders change the functionality and integrity of the BBB. Glucocorticoids are being used sucessfully in the treatment of some disorders while their effects on others are questionable. In addition, conflicting results between clinical and experimental experience using animal models has arisen, so that the results of molecular studies in animal models need to be revisited in an appropriate in vitro model of the human BBB for more effective treatment strategies. Using the human brain microvascular endothelial cell line hCMEC/D3, the influence of glucocorticoids on the expression of barrier constituting adherens junction and tight junction transmembrane proteins (VE-cadherin, occludin, claudins) was investigated and compared to other established BBB models. In hCMEC/D3 cells the administration of glucocorticoids induced expression of the targets occludin 2.75 +/- 0.04-fold and claudin-5 up to 2.32 +/- 0.11-fold, which is likely to contribute to the more than threefold enhancement of transendothelial electrical resistance reflecting barrier tightness. Our analyses further provide direct evidence that the GC hydrocortisone prevents endothelial barrier breakdown in response to pro-inflammatory stimuli (TNFalpha administration), which could be demonstrated to be partly based on maintenance of occludin levels. Our studies strongly suggest stabilization of BBB function as a mode of GC action on a molecular level in the human brain vasculature.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Fluids Barriers CNS
                Journal ID (iso-abbrev): Fluids Barriers CNS
                Title: Fluids and Barriers of the CNS
                Publisher: BioMed Central
                ISSN (Electronic): 2045-8118
                Publication date Collection: 2013
                Publication date (Electronic): 26 March 2013
                Volume: 10
                Page: 16
                Affiliations
                [1 ]Weill Cornell Medical College, New York, NY, USA
                [2 ]Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, U.K
                [3 ]Inserm, U1016, Institut Cochin, Paris, France
                [4 ]CNRS, UMR8104, Paris, France
                [5 ]Université Paris Descartes, Sorbonne Paris Cité, Paris, France
                Article
                Publisher ID: 2045-8118-10-16
                DOI: 10.1186/2045-8118-10-16
                PMC ID: 3623852
                PubMed ID: 23531482
                SO-VID: 3a9ff24c-4971-4d69-a8cf-4b5c2b919ac9
                Copyright © Copyright ©2013 Weksler et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 5 December 2012
                Date accepted : 25 February 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Neurology
                Keywords: blood–brain barrier,brain endothelium,immortalized cell line,in vitro model
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: blood–brain barrier, brain endothelium, immortalized cell line, in vitro model

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