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Cells
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Blood–Brain Barrier: From Physiology to Disease and Back
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Blood–Brain Barrier: From Physiology to Disease and Back

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 15255

Special Issue Editor

Prof. Dr. Bingmei Fu

E-Mail Website
Guest Editor
Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, USA
Interests: the blood–brain barrier; glycocalyx; vascular permeability; vascular signaling; tumor metastasis via microcirculation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The blood–brain barrier (BBB) is the interface between the central nervous system (CNS) and the cerebral blood circulation. It is a dynamic barrier essential for maintaining the microenvironment of the brain. Compromised BBBs have been found in various neurological disorders including schizophrenia, autism, Alzheimer’s disease, and brain tumors, to name a few. Recent advances in directing human-induced pluripotent stem cells (hiPSCs) to differentiate and generate patient-specific BBBs provide an exciting opportunity to investigate disease mechanisms responsible for these compromised BBBs. The biomimetic BBBs derived from hiSPCs not only enable the cost-effective development of systemic drug delivery methods but also drug screening targeting the neurovascular coupling for these neurological disorders. This Special Issue thus aims to collect contributions on topics including 1) the development and characterization of the BBB from primary and hiPSC-derived cells, as well as cell lines in health and disease; 2) the investigation of molecular and cellular mechanisms for compromised BBBs in neurological disorders; 3) the development of methods for drug delivery across the BBB; 4) drug screening utilizing the developed BBBs for the treatment of neurological disorders; and 5) the investigation of immune- and tumor-cell adhesion to and transmigration across the BBB. Although original contributions are preferred, focused review articles are also welcome.

Dr. Bingmei Fu
Guest Editor

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Keywords

  • human-induced pluripotent stem-cell-derived blood–brain barrier
  • molecular structure of blood–brain barrier
  • blood–brain barrier permeability
  • modulation of blood–brain barrier
  • drug delivery via blood–brain barrier
  • blood–brain barriers on-a-chip
  • biomimetic blood–brain barriers for neurological disorders
  • adhesion and transmigration across the blood–brain barrier
  • neurovascular coupling
  • regenerative medicine

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Published Papers (4 papers)

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Research

17 pages, 4119 KiB  
Article
Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
by Yunfei Li, Zhixiong Sun, Huixiang Zhu, Yan Sun, David B. Shteyman, Sander Markx, Kam W. Leong, Bin Xu and Bingmei M. Fu
Cells 2023, 12(3), 422; https://doi.org/10.3390/cells12030422 - 27 Jan 2023
Cited by 4 | Viewed by 2167
Abstract
We have previously established that the integrity of the induced blood–brain barrier (iBBB) formed by brain microvascular endothelial cells derived from the iPSC of 22q11.2 DS (22q11.2 Deletion Syndrome, also called DiGeorge Syndrome) patients is compromised. We tested the possibility that the haploinsufficiency [...] Read more.
We have previously established that the integrity of the induced blood–brain barrier (iBBB) formed by brain microvascular endothelial cells derived from the iPSC of 22q11.2 DS (22q11.2 Deletion Syndrome, also called DiGeorge Syndrome) patients is compromised. We tested the possibility that the haploinsufficiency of CRKL, a gene within the 22q11.2 DS deletion region, contributes to the deficit. The CRKL is a major substrate of the Abl tyrosine kinase, and the Abl/CRKL signaling pathway is critical for endothelial barrier functions. Imatinib, an FDA-approved drug, inhibits Abl kinase and has been used to treat various disorders involving vascular leakages. To test if imatinib can restore the compromised iBBB, we treated the patient’s iBBB with imatinib. After treatment, both trans-endothelial electrical resistance and solute permeability returned to comparable levels of the control iBBB. Correspondingly, changes in tight junctions and endothelial glycocalyx of the iBBB were also restored. Western blotting showed that imatinib increased the level of active forms of the CRKL protein. A transcriptome study revealed that imatinib up-regulated genes in the signaling pathways responsible for the protein modification process and down-regulated those for cell cycling. The KEGG pathway analysis further suggested that imatinib improved the gene expression of the CRKL signaling pathway and tight junctions, which agrees with our expectations and the observations at protein levels. Our results indicate that the 22q11.2DS iBBB is at least partially caused by the haploinsufficiency of CRKL, which can be rescued by imatinib via its effects on the Abl/CRKL signaling pathway. Our findings uncover a novel disease mechanism associated with 22q11.2DS. Full article
(This article belongs to the Special Issue Blood–Brain Barrier: From Physiology to Disease and Back)
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14 pages, 3335 KiB  
Article
Morphological and Functional Effects of Ultrasound on Blood–Brain Barrier Transitory Opening: An In Vitro Study on Rat Brain Endothelial Cells
by Jacopo Junio Valerio Branca, Matteo Boninsegna, Gabriele Morucci, Donatello Carrino, Claudio Nicoletti, Ferdinando Paternostro, Massimo Gulisano, Leonardo Bocchi and Alessandra Pacini
Cells 2023, 12(1), 192; https://doi.org/10.3390/cells12010192 - 3 Jan 2023
Cited by 1 | Viewed by 2452
Abstract
With the recent advances in medicine, human life expectancy is increasing; however, the extra years of life are not necessarily spent in good health or free from disability, resulting in a significantly higher incidence of age-associated pathologies. Among these disorders, neurodegenerative diseases have [...] Read more.
With the recent advances in medicine, human life expectancy is increasing; however, the extra years of life are not necessarily spent in good health or free from disability, resulting in a significantly higher incidence of age-associated pathologies. Among these disorders, neurodegenerative diseases have a significant impact. To this end, the presence of the protective blood–brain barrier (BBB) represents a formidable obstacle to the delivery of therapeutics. Thus, this makes it imperative to define strategies to bypass the BBB in order to successfully target the brain with the appropriate drugs. It has been demonstrated that targeting the BBB by ultrasound (US) can transiently make this anatomical barrier permeable and in so doing, allow the delivery of therapeutics. Thus, our aim was to carry out an in depth in vitro molecular and morphological study on the effects of US treatment on the BBB. The rat brain endothelial (RBE4) cell line was challenged with exposure to 12 MHz diagnostic US treatment for 10, 20, and 30 min. Cell viability assays, Western blotting analysis on the endoplasmic reticulum (ER), and oxidative stress marker evaluation were then performed, along with cytological and immunofluorescence staining, in order to evaluate the effects of US on the intercellular spaces and tight junction distribution of the brain endothelial cells. We observed that the US treatment exerted no toxic effects on either RBE4 cell viability or the upregulation/dislocation of the ER and oxidative stress marker (GRP78 and cytochrome C, respectively). Further, we observed that the application of US induced an increase in the intercellular spaces, as shown by Papanicolaou staining, mainly due to the altered distribution of the tight junction protein zonula occludens-1 (ZO-1). This latter US-dependent effect was transient and disappeared 20 min after the removal of the stimulus. In conclusion, our results show that US induces a transient alteration of the BBB, without altering the intracellular signaling pathways such as the ER and oxidative stress that could potentially be toxic for endothelial cells. These results suggested that US treatment could represent a potential strategy for improving drug delivery to the brain. Full article
(This article belongs to the Special Issue Blood–Brain Barrier: From Physiology to Disease and Back)
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20 pages, 4786 KiB  
Article
A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs
by Leopold Koenig, Anja Patricia Ramme, Daniel Faust, Manuela Mayer, Tobias Flötke, Anna Gerhartl, Andreas Brachner, Winfried Neuhaus, Antje Appelt-Menzel, Marco Metzger, Uwe Marx and Eva-Maria Dehne
Cells 2022, 11(20), 3295; https://doi.org/10.3390/cells11203295 - 19 Oct 2022
Cited by 18 | Viewed by 5463
Abstract
Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of [...] Read more.
Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood–brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier. Full article
(This article belongs to the Special Issue Blood–Brain Barrier: From Physiology to Disease and Back)
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32 pages, 12535 KiB  
Article
Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity
by Rekha Jagadapillai, Xiaolu Qiu, Kshama Ojha, Zhu Li, Ayman El-Baz, Shipu Zou, Evelyne Gozal and Gregory N. Barnes
Cells 2022, 11(14), 2211; https://doi.org/10.3390/cells11142211 - 15 Jul 2022
Cited by 8 | Viewed by 4280
Abstract
Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was [...] Read more.
Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was queried for individuals with a copy number variation (CNV) on microarray, Vineland, and Parent Concern Questionnaire scores. Pathway analyses of genes from pathogenic CNVs yielded 659 genes whose protein–protein interactions and mRNA expression mapped 121 genes with maximal antenatal expression in 12 brain regions. A Research Domain Criteria (RDoC)-derived neural circuits map revealed significant differences in anxiety, motor, and activities of daily living skills scores between altered CNV genes and normal microarrays subjects, involving Positive Valence (reward), Cognition (IQ), and Social Processes. Vascular signaling was identified as a biological process that may influence these neural circuits. Neuroinflammation, microglial activation, iNOS and 3-nitrotyrosine increase in the brain of Semaphorin 3F- Neuropilin 2 (Sema 3F-NRP2) KO, an ASD mouse model, agree with previous reports in the brain of ASD individuals. Signs of platelet deposition, activation, release of serotonin, and albumin leakage in ASD-relevant brain regions suggest possible blood brain barrier (BBB) deficits. Disruption of neurovascular signaling and BBB with neuroinflammation may mediate causative pathophysiology in some ASD subgroups. Although preliminary, these data demonstrate the potential for developing novel therapeutic strategies based on clinically derived data, genomics, cognitive neuroscience, and basic neuroscience methods. Full article
(This article belongs to the Special Issue Blood–Brain Barrier: From Physiology to Disease and Back)
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