scholarly journals The Blood–Brain Barrier, an Evolving Concept Based on Technological Advances and Cell–Cell Communications

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 133
Author(s):  
Camille Menaceur ◽  
Fabien Gosselet ◽  
Laurence Fenart ◽  
Julien Saint-Pol
Keyword(s):  
Blood Brain Barrier ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Cell Communication ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
History Of ◽  
The Brain ◽  
Cell Cell

The construction of the blood–brain barrier (BBB), which is a natural barrier for maintaining brain homeostasis, is the result of a meticulous organisation in space and time of cell–cell communication processes between the endothelial cells that carry the BBB phenotype, the brain pericytes, the glial cells (mainly the astrocytes), and the neurons. The importance of these communications for the establishment, maturation and maintenance of this unique phenotype had already been suggested in the pioneering work to identify and demonstrate the BBB. As for the history of the BBB, the evolution of analytical techniques has allowed knowledge to evolve on the cell–cell communication pathways involved, as well as on the role played by the cells constituting the neurovascular unit in the maintenance of the BBB phenotype, and more particularly the brain pericytes. This review summarises the key points of the history of the BBB, from its origin to the current knowledge of its physiology, as well as the cell–cell communication pathways identified so far during its development, maintenance, and pathophysiological alteration.

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

2018 ◽  
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 ◽  
Pluripotent Stem Cells ◽  
Neurovascular Unit ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
The Brain

ABSTRACTBrain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

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 Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

2020 ◽  
Vol 11 ◽  
Author(s):  
Keqing Nian ◽  
Ian C. Harding ◽  
Ira M. Herman ◽  
Eno E. Ebong
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
The United States ◽  
Brain Barrier ◽  
Endothelial Glycocalyx ◽  
Altered Expression ◽  
Blood Brain

Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

scholarly journals Neurological Diseases in Relation to the Blood–Brain Barrier

2012 ◽  
Vol 32 (7) ◽  
pp. 1139-1151 ◽  
Author(s):  
Gary A Rosenberg
Keyword(s):  
Free Radicals ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Cellular Damage ◽  
Brain Diseases ◽  
Acute Injury ◽  
Blood Brain ◽  
The Brain

Disruption of the blood–brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.

scholarly journals Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7710
Author(s):  
Ying-Chieh Wu ◽  
Tuuli-Maria Sonninen ◽  
Sanni Peltonen ◽  
Jari Koistinaho ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Blood Brain Barrier ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Induced Pluripotent Stem Cell ◽  
Brain Barrier ◽  
Blood Brain ◽  
Induced Pluripotent ◽  
The Brain

The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

scholarly journals Lab-on-a-Chip Platforms as Tools for Drug Screening in Neuropathologies Associated with Blood–Brain Barrier Alterations

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 916
Author(s):  
Cristina Elena Staicu ◽  
Florin Jipa ◽  
Emanuel Axente ◽  
Mihai Radu ◽  
Beatrice Mihaela Radu ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
High Throughput ◽  
High Throughput Screening ◽  
Biomedical Applications ◽  
Neurovascular Unit ◽  
Lab On A Chip ◽  
Brain Barrier ◽  
Blood Brain ◽  
Pharmacological Screening ◽  
The Brain

Lab-on-a-chip (LOC) and organ-on-a-chip (OOC) devices are highly versatile platforms that enable miniaturization and advanced controlled laboratory functions (i.e., microfluidics, advanced optical or electrical recordings, high-throughput screening). The manufacturing advancements of LOCs/OOCs for biomedical applications and their current limitations are briefly discussed. Multiple studies have exploited the advantages of mimicking organs or tissues on a chip. Among these, we focused our attention on the brain-on-a-chip, blood–brain barrier (BBB)-on-a-chip, and neurovascular unit (NVU)-on-a-chip applications. Mainly, we review the latest developments of brain-on-a-chip, BBB-on-a-chip, and NVU-on-a-chip devices and their use as testing platforms for high-throughput pharmacological screening. In particular, we analyze the most important contributions of these studies in the field of neurodegenerative diseases and their relevance in translational personalized medicine.

scholarly journals Advancements in the Blood–Brain Barrier Penetrating Nanoplatforms for Brain Related Disease Diagnostics and Therapeutic Applications

Polymers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3055
Author(s):  
Suresh Thangudu ◽  
Fong-Yu Cheng ◽  
Chia-Hao Su
Keyword(s):  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Drug Transport ◽  
Current Knowledge ◽  
Brain Barrier ◽  
Therapeutic Drugs ◽  
Blood Brain ◽  
Disease Diagnostics ◽  
The Brain ◽  
Significant Attention

Noninvasive treatments to treat the brain-related disorders have been paying more significant attention and it is an emerging topic. However, overcoming the blood brain barrier (BBB) is a key obstacle to most of the therapeutic drugs to enter into the brain tissue, which significantly results in lower accumulation of therapeutic drugs in the brain. Thus, administering the large quantity/doses of drugs raises more concerns of adverse side effects. Nanoparticle (NP)-mediated drug delivery systems are seen as potential means of enhancing drug transport across the BBB and to targeted brain tissue. These systems offer more accumulation of therapeutic drugs at the tumor site and prolong circulation time in the blood. In this review, we summarize the current knowledge and advancements on various nanoplatforms (NF) and discusses the use of nanoparticles for successful cross of BBB to treat the brain-related disorders such as brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke.

scholarly journals Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

2016 ◽  
Vol 36 (9) ◽  
pp. 1481-1507 ◽  
Author(s):  
Ralf G Rempe ◽  
Anika MS Hartz ◽  
Björn Bauer
Keyword(s):  
Matrix Metalloproteinases ◽  
Blood Brain Barrier ◽  
Cancer Metastasis ◽  
Current Knowledge ◽  
Cerebral Aneurysms ◽  
The Body ◽  
Brain Barrier ◽  
Brain Disorders ◽  
Blood Brain ◽  
The Brain

Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood–brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood–brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer’s disease, Parkinson’s disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood–brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood–brain barrier in brain disorders.

scholarly journals Pathology of the neurovascular unit in leukodystrophies

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Parand Zarekiani ◽  
Marjolein Breur ◽  
Nicole I. Wolf ◽  
Helga E. de Vries ◽  
Marjo S. van der Knaap ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Barrier Function ◽  
Neurovascular Unit ◽  
Underlying Disease ◽  
Aquaporin 4 ◽  
Brain Barrier ◽  
Comprehensive Overview ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

AbstractThe blood–brain barrier is a dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma. Specialized brain endothelial cells, astrocytes, neurons, microglia and pericytes together compose the neurovascular unit and interact to maintain blood–brain barrier function. A disturbed brain barrier function is reported in most common neurological disorders and may play a role in disease pathogenesis. However, a comprehensive overview of how the neurovascular unit is affected in a wide range of rare disorders is lacking. Our aim was to provide further insights into the neuropathology of the neurovascular unit in leukodystrophies to unravel its potential pathogenic role in these diseases. Leukodystrophies are monogenic disorders of the white matter due to defects in any of its structural components. Single leukodystrophies are exceedingly rare, and availability of human tissue is unique. Expression of selective neurovascular unit markers such as claudin-5, zona occludens 1, laminin, PDGFRβ, aquaporin-4 and α-dystroglycan was investigated in eight different leukodystrophies using immunohistochemistry. We observed tight junction rearrangements, indicative of endothelial dysfunction, in five out of eight assessed leukodystrophies of different origin and an altered aquaporin-4 distribution in all. Aquaporin-4 redistribution indicates a general astrocytic dysfunction in leukodystrophies, even in those not directly related to astrocytic pathology or without prominent reactive astrogliosis. These findings provide further evidence for dysfunction in the orchestration of the neurovascular unit in leukodystrophies and contribute to a better understanding of the underlying disease mechanism.

scholarly journals Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level

2021 ◽  
Vol 22 (7) ◽  
pp. 3742
Author(s):  
Sweilem B. Al Rihani ◽  
Lucy I. Darakjian ◽  
Malavika Deodhar ◽  
Pamela Dow ◽  
Jacques Turgeon ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transporters ◽  
Neurovascular Unit ◽  
Drug Distribution ◽  
Drug Efficacy ◽  
Brain Barrier ◽  
Protective Function ◽  
Transporter Protein ◽  
Blood Brain ◽  
The Brain

The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer’s disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity.

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