Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

AbstractChallenges in drug development of neurological diseases remain mainly ascribed to the blood–brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions. We demonstrate on-chip mimicry of the BBB structure and function by cellular interactions, key gene expressions, low permeability, and 3D astrocytic network with reduced reactive gliosis and polarized aquaporin-4 (AQP4) distribution. Moreover, our model precisely captures 3D nanoparticle distributions at cellular levels and demonstrates the distinct cellular uptakes and BBB penetrations through receptor-mediated transcytosis. Our BBB platform may present a complementary in vitro model to animal models for prescreening drug candidates for the treatment of neurological diseases.

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Structure and function of the blood–brain barrier

Neurobiology of Disease ◽

10.1016/j.nbd.2009.07.030 ◽

2010 ◽

Vol 37 (1) ◽

pp. 13-25 ◽

Cited By ~ 2151

Author(s):

N. Joan Abbott ◽

Adjanie A.K. Patabendige ◽

Diana E.M. Dolman ◽

Siti R. Yusof ◽

David J. Begley

Keyword(s):

Blood Brain Barrier ◽

Structure And Function ◽

Brain Barrier ◽

Blood Brain ◽

And Function

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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Overview of the Structure and Function of the Blood-Brain Barrier in vivo

Blood—Brain Barrier ◽

10.1007/978-1-4615-0579-2_1 ◽

2001 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Joseph D. Fenstermacher ◽

Tavarekere Nagaraja ◽

Kenneth R. Davies

Keyword(s):

Blood Brain Barrier ◽

Structure And Function ◽

Brain Barrier ◽

Blood Brain ◽

And Function

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In Vitro Blood–Brain Barrier-Integrated Neurological Disorder Models Using a Microfluidic Device

Micromachines ◽

10.3390/mi11010021 ◽

2019 ◽

Vol 11 (1) ◽

pp. 21 ◽

Cited By ~ 4

Author(s):

Jin-Ha Choi ◽

Mallesh Santhosh ◽

Jeong-Woo Choi

Keyword(s):

Blood Brain Barrier ◽

Neurological Disorder ◽

Neurological Diseases ◽

Critical Role ◽

Microfluidic System ◽

Brain Barrier ◽

Human Organ ◽

Blood Brain ◽

Screening Platform

The blood–brain barrier (BBB) plays critical role in the human physiological system such as protection of the central nervous system (CNS) from external materials in the blood vessel, including toxicants and drugs for several neurological disorders, a critical type of human disease. Therefore, suitable in vitro BBB models with fluidic flow to mimic the shear stress and supply of nutrients have been developed. Neurological disorder has also been investigated for developing realistic models that allow advance fundamental and translational research and effective therapeutic strategy design. Here, we discuss introduction of the blood–brain barrier in neurological disorder models by leveraging a recently developed microfluidic system and human organ-on-a-chip system. Such models could provide an effective drug screening platform and facilitate personalized therapy of several neurological diseases.

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Methamphetamine effects on blood-brain barrier structure and function

Frontiers in Neuroscience ◽

10.3389/fnins.2015.00069 ◽

2015 ◽

Vol 9 ◽

Cited By ~ 54

Author(s):

Nicole A. Northrop

Keyword(s):

Blood Brain Barrier ◽

Structure And Function ◽

Brain Barrier ◽

Barrier Structure ◽

Blood Brain ◽

And Function

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Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Biomedicines ◽

10.3390/biomedicines9070837 ◽

2021 ◽

Vol 9 (7) ◽

pp. 837

Author(s):

Takashi Fujimoto ◽

Yoichi Morofuji ◽

Andrej Kovac ◽

Michelle A. Erickson ◽

Mária A. Deli ◽

...

Keyword(s):

Blood Brain Barrier ◽

Neurological Diseases ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Neuroprotective Effects ◽

Blood Brain ◽

Mouse Brain Endothelial Cells ◽

Pharmacological Significance ◽

Primary Mouse

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood–brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases.

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