Journal of Alzheimers & Neurodegenerative Diseases Category: Clinical Type: Review Article
Fundamental Neurovascular Components for the Development of Complex and Dynamic in Vitro Brain Equivalent Models
- Goodwell Nzou1*, Michael C Seeds1, Robert T Wicks1, Anthony J Atala1
- 1 Wake Forest Institute For Regenerative Medicine, Wake Forest School Of Medicine, Winston-Salem. NC 27101, United States
*Corresponding Author:Goodwell Nzou
Wake Forest Institute For Regenerative Medicine, Wake Forest School Of Medicine, Winston-Salem. NC 27101, United States
Received Date: May 06, 2019 Accepted Date: Jun 17, 2019 Published Date: Jun 24, 2019
Current in vivo and in vitro models
Cell type limitations in current models
The blood-brain barrier
FUNCTIONS OF NEUROVASCULAR UNIT COMPONENTS
Human brain microvascular endothelial cells
BBB properties exhibited by brain endothelial cells is mainly controlled by tight junctions containing junctional adhesion molecules arranged in a polarized manner between adjacent brain endothelial cells as shown if Figure 4. Junctional adhesion molecules are located on the luminal side while cadherins are on the abluminal side. Between the luminal and the abluminal are the tight junction proteins that creates a tight seal preventing free paracellular transport. Claudins are the main tight junctional protein that define BBB maturation [55-57]. Brain endothelial cells mainly express claudin 1, 3, 5 and 12 [57-60]. These tetraspan transmembrane proteins assist in the construction of the BBB and hence the maintenance of barrier integrity between adjacent endothelial cells . Claudin 5 is regulated by β-catenin, however, it is inhibited by β-catenin when the transcriptional factor FOXO-1 that is induced by VEGF signaling is active in brain endothelial cells [56,61]. This regulation in endothelial cells determines BBB maturation.
Even though occludin expression in brain endothelial cells has been shown to decrease barrier integrity in vitro [62,63], occludin deficient mice had normal barrier function and the tight junction morphology was maintained .
The tight junctions (claudins and occludin) are anchored to the actin cytoskeleton by the Zonula occludens. Specifically, Zonula occluden-1 (ZO-1) is a membrane-associated granulate kinase like protein. ZO-1 stabilization of tight junctions is critical such that its deletion leads to increased permeability due to the disruption of the tight junction and redistribution of active myosin II .
Interestingly, barrier formation is evident between three adjoining endothelial cells as well. Specifically, tricellulin [66,67] and lipolysis stimulated lipoprotein receptor  are located at the point of connection between three cells. These are weak tri-cellular junctions; however, they stabilize the specialized junctions in epithelial cells.
Vascular endothelial cadherin (VE-cadherin) in endothelial cells controls permeability and also prevents leukocyte extravasation into the brain parenchyma . Furthermore, VE- cadherin and N- cadherin function as adhesion receptors and are involved in downstream signaling via complexes of proteins bound to their cytosolic tails. N-cadherin in particular, mediates cell-cell interaction between endothelial cells and pericytes . Β-catenin is also expressed by endothelial cells and is implicated in barrier functions. Its function as a co-transcriptional factor are critical in protein expression of claudin-5 , but its concerted anchoring of VE-cadherin with its homologue plakoglobin/γ-catenin to actin microfilaments stabilizes the junctional proteins and thereby improves barrier properties .
Brain endothelial cells have relatively large quantities and volumes of mitochondria compared to peripheral endothelial cells. This is because they contain enzymes and active transport systems that rely either directly on ATP consumption or on a secondary active transport systems that depend on the electrochemical gradient generated by active transporters . Facilitated and active transporters at the BBB include glucose transporter-1 (GLUT-1) [73-75], permeability glycoprotein- (P-gp) also known as multidrug resistant protein 1 (Mdr-1), and breast cancer resistant protein (BCRP) that are critical in efflux of harmful hydrophilic and hydrophobic xenobiotics from the brain parenchyma [76-78]. In addition, however, they also serve to efflux many pharmaceutical compounds, limiting their therapeutic value.
Low transcellular transport at the BBB is governed by low numbers of caveolae and reduced transcellular transporters such as major facilitator superfamily domain-containing protein -2 (MFSD2 or MFSD2A) [79,80]. Specifically, MFSD2A is an DHA omega3 fatty acid transporter in endothelial cells where it regulates vesicular traffic in CNS BBB/blood retinal barrier (BRB) [81,82]. Systemic ablation of MFSD2A increased BBB permeability due to uncontrolled vesicular trafficking in endothelial cells . Caveolin-1 regulates signal transduction, endocytosis, transcytosis and molecular transport. It also controls angiogenic response through mediating VEGF receptor 2 (VEGFR2) phosphorylation and internalization [49,70,84]. Caveolin-1; however, contributes to junctional opening by weakening VE-cadherin based adherens junction by interacting with β-catenin. Under inflammatory conditions, the pro inflammatory chemokine CCL2 induces BBB disruption through CAV-1 mediated internalization of occludin and claudin-5 .
Enzymes that make chemical modifications to molecules that may cross the BBB and affect neuronal function are also prevalent in brain endothelial cells. These chemical modifications reduce toxicity of molecules by either metabolism that renders the molecules inactive or by addition of moieties that directs the toxins towards excretory pathways [87,88]. Specifically, brain endothelial cells have high concentrations of γ-glutamyl transpeptidase, alkaline phosphatase and aromatic acid decarboxylases . Together with active transporters, these metabolic barriers regulates the concentrations of ions, metabolites and foreign substances within the NVU [74,90].
Many current three-dimensional models consist of artificial polycarbonate, polytetrafluorethylene, and polydimethyl-siloxane membranes serving as basal lamina [5,30,109], which is not reflective of the human brain ECM. Even though the use of collagen (usually type I) to provide a 3D microenvironment for glial cells and neurons  allows for the fabrication of multi cellular in-vitro models, it is important to note that no collagen I and very low amounts of collagen type 4 are found in the adult human brain. The ECM in the adult brain tissue consists of lecticans, a family of proteoglycans that contain lectin and hyaluronic acid domains . Incorporation of such ECM may promote BBB maturation that recapitulates normal human physiology.
Microglial involvement in brain injuries has been investigated but there are very few studies that have been conducted to delineate a direct link between microglia and BBB maintenance. Glial involvement in BBB maintenance has mostly been attributed to astrocytes because their end feet processes touch the microvessels. Findings on microglial location in the perivascular space highlight their interaction with endothelial cells and supports their influence on BBB integrity. During their resting phase, microglial cells effectively control the neurovascular unit microenvironment. Nimmerjahn and colleagues, have shown that microglia clear the parenchyma of accumulated low diffusible metabolic products and tissue component debris . They observed bulbous branch endings and spontaneous engulfment of tissue components. Further histologic staining highlighted microglial processes and protrusions in contact with neuronal cell bodies and blood vessels . This indicates that under healthy conditions, microglia interact with other cortical elements and regulate the NVU microenvironment by clearing debris and cellular components. However, it should be noted that upon activation, microglia release cytokines such as TNF-α and IL-6 that have been associated with BBB dysfunction [130,131]. Further discussion on microglia involvement in disease states will be included below in specific disease sections of this report. However, more studies are needed to elucidate the direct interaction between microglia and cells of the BBB in order to fully understand the involvement of microglia in BBB maintenance. Current in vitro neurovascular unit models do not consist of microglia, in contrast to our current model.
BBB DYSFUNCTION IN NEURODEGENERATIVE DISEASES
Over 20 independent postmortem studies have confirmed BBB breakdown in AD . Hallmarks of BBB dysfunction include, pericytes and endothelial cell degeneration, loss of tight junctions, red blood cell and monocyte extravasation, brain capillary leakages of blood borne components such as albumin, immunoglobulin (IgG), fibrinogen, and thrombin . There are many mechanisms that contribute to BBB breakdown in AD. Some of these processes include early cerebrovascular disorder , vascular dysregulation , and ischemic damage .
Though many causes of AD have not been linked to specific genetic causes, transgenic animal models are prevalently used to study Alzheimer’s disease [122,159-162]. Mice with mutations in the APP gene, which produces the amyloid precursor protein that is in turn processed into fragments including amyloid beta (Aβ) peptide, have been shown to have capillary leakages of blood derived fibrinogen, IgG and albumin, and leakage of experimentally injected Evans blue dyes. Electron microscopy of these mouse brains also indicated degeneration and loss of pericytes, endothelium, and vascular smooth muscles cells [163-167]. Time course studies evaluating BBB breakdown, with respect to other pathologies, indicated that BBB breakdown develops early in APP transgenic mice [52,166-168]. Deane and colleagues observed aberrant expression of low-density lipoprotein transporter protein1 (LRP1) in APP transgenic mice . This transporter is a major efflux protein for Aβ toxin at the BBB. Other studies with an APP model showed an increase in expression of an influx transporter, the receptor for advanced glycation end products (RAGE) . Normal function of transporters such as LRP1 and RAGE at the BBB is crucial for maintaining brain homeostasis.
Cerebrovascular autoregulation is impaired in APP murine models . For example, studies have shown reduced brain glucose uptake due to glucose transporter dysfunction in APP transgenic models[171,172]. BBB breakdown and inhibition of LRP1 transcription due to diminished GLUT1 expression in brain endothelial cells is thought to accelerate Aβ pathology . Alterations in protein expression of all these crucial transporters at the BBB can result in a malfunctioning BBB that can lead to deleterious secondary consequences.
BBB breakdown has been shown in many other transgenic murine models representing known or suspected genetic associations from human studies. For examples, loss of BBB integrity  and loss of vascular phenotype  in mice expressing PSEN1 mutation, BBB breakdown in Tau transgenic mice , Pericyte degeneration and BBB dysfunction in PDGFRβ- deficient transgenic mice , and accumulation of perivascular IgG, fibrinogen, thrombin, hemosiderin deposits and leakage of Evans blue in APOE transgenic mice . Even though no effective treatment has been developed from any of these animal models, it is worth noting that the models have increased our understanding of molecular pathways in brain cellular functions and may possibly help to identify biomarkers for early Alzheimer’s disease diagnosis.
Importantly, neuroimaging in patients with mild cognitive impairment revealed that BBB breakdown precedes brain atrophy or dementia [168,176-178]. Further studies and new models are still needed to determine cellular and molecular mechanism by which the BBB is impaired and to accelerate the development of therapeutic targets for Alzheimer’s disease that aim to maintain and repair BBB integrity.
While some studies in animal models assume that BBB integrity remains unchanged during the development of PD pathology [188,189], clinical evidence shows increased BBB permeability in PD patients [190-193]. PD patients have been shown to have reduced P-glycoprotein (P-gp) function [191,194]. Studies in P-gp knock-out mice have shown an increased parenchymal accumulation of administered neurotoxins, ivermectin and the carcinostatic vinblanstine. Hence normal P-gp function at the BBB appears compromised in PD . Furthermore, diminished P-gp activity in aged people is associated with reduced removal of toxins from the brain and linked to PD pathology . Since PD is a chronic neurodegenerative disorder that affects one in every 100 people at the age of 60 and above, it is worth pointing out that many age related processes, such as increased production of ROS and proinflammatory cytokines in brain endothelial cells, contribute heavily towards BBB dysfunction [196-198]. Since neurons and other parenchymal cells are mainly affected in PD and other age-related dementias, it is critical that in vitro models designed to understand molecular involvement of the BBB in PD contain these cell types.
The transmigration of leukocytes highlights the importance of maintaining BBB integrity in MS. Neuroimaging studies and postmortem findings in MS patients show that BBB disruption is an early feature in MS  and animal studies have shown that BBB breakdown precedes leukocyte infiltration [47,83]. Spencer and colleagues speculated that environmental and genetic associations may influence the BBB, which results in the vessel pathology of the disease . In order to elucidate the mechanistic involvement of the BBB in MS pathology, new in vitro models that contain vascular cells and neuro-glial components such as oligodendrocytes and neurons are critical to model a functional BBB. Such models can be applied to assess transmigration of leukocytes. Models containing a functional BBB can be used to identify disease initiating microenvironmental factors, such as changes in cytokine levels, that activate circulating leukocytes and initiate adhesion. Further, such models could be utilized to investigate pathological connections between BBB integrity and demyelination that occurs in MS. Current in vitro models of the NVU do not contain oligodendrocytes or neuronal cells types, which makes it difficult to study MS disease conditions comprehensively in vitro.
NVU CONTAINING A FUNCTIONAL BBB
We have highlighted above that BBB breakdown precedes brain atrophy and leucocyte infiltration in Alzheimer’s and MS respectively. Upon investigating BBB integrity, our data from this organoid model show transmigration of 70 kDa dextran and IgG when the BBB is transiently disrupted using histamine or hypoxia. Further studies are needed to assess the link between BBB leakage and neurological disorders. Current APOE transgenic mice models also show accumulation of perivascular IgG, fibrinogen, thrombin, hemosiderin deposits and leakage of Evans blue into the brain parenchyma. A model containing functional BBB and neuro-glia components may help elucidate the link between BBB disruption and Alzheimer’s disease and related dementias. Our data also show the disruption of tight junctions when the organoids are cultured under hypoxic conditions. This indicates the utility of the model in understanding the underlying physiological conditions that alter normal NVU microenvironment that could possibly cause BBB breakdown in neurological disorders. Further evaluation of this model is required to ascertain its utility in neurodegenerative disease modeling.
In this review we have described the importance of the integrated function of the cell types that make up the BBB with parenchymal cells such as glia and neurons. We have discussed the limitation of 2D models that do not recapitulate the basic functions of the BBB. 2D cell cultures are limited in disease modeling applications because they do not allow for the incorporation of more than 3 cell types without losing the proper 3D microenvironment required to recapitulate normal physiological function of each of the cell types. We also highlighted the fact that most current models incorporate three major cell types that form the BBB or use rodent cells to imply human BBB physiology and functionality. We propose that the use of these models in preclinical studies may not fully represent normal NVU physiology activity. Specifically, receptor and enzyme systems that regulate the influx and efflux of substances at the BBB level are different between species and hence extrapolation of BBB functionality from rodents needs to be done with caution and/or with a fair understanding of these differences. For example, studies have shown that some radio ligands that are substrates for P-gp in rodents are efficiently exported in rodents . Similar studies, however, have shown that these radio ligands are taken up and retained by the brain in humans and non-human primates [212-214]. Furthermore, we have also stated that the utilization of synthetic membranes to establish the basement membrane is limiting for they impede important intercellular interactions that are critical for the normal function of the neurovascular unit to maintain BBB integrity. However, new models consisting of electro spun membranes derived from human ECM may enhance the development of physiologically relevant NVU model.
Treatment schemes that are best suited for an individual based on pharmacogenetic and pharmacogenomic information have been reported for cancer [215-218]. This theme of personalized medicine could prove to be very effective in genetically influenced neurological diseases [219-221]. To pave the way for extensive studies, in vitro models containing patient derived cells could be utilized not only to identify therapeutic targets that are specific to the individual or group of individuals that express specific genotypes but would also aid the understanding of molecular and biochemical basis of drug efficacy. Future studies incorporating patient derived cells into an organoid system containing the major components of the NVU could elucidate mechanistic connections between BBB dysfunction and disease progression. Patient derived cells of all cell types composing the NVU are not readily available. In addition, efficient methods of deriving all six cell types composing the NVU through the use of induced pluripotent stem cell (iPSC) technology have not been developed to date. To overcome this limitation, gene editing tools could be employed to create mutations in specific cell types prior to incorporating them into an organoid. The organoid could then be evaluated for that disease phenotype.
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Citation:Nzou G, Seeds MC, Wicks RT, Atala AJ (2019) Fundamental Neurovascular Components for the Development of Complex and Dynamic in Vitro Brain Equivalent Models. J Alzheimers Neurodegener Dis 5: 021.
Copyright: © 2019 Goodwell Nzou, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.