scholarly journals Investigation of Neurodevelopmental Deficits of 22 q11.2 Deletion Syndrome with a Patient-iPSC-Derived Blood–Brain Barrier Model

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2576
Author(s):  
Yunfei Li ◽  
Yifan Xia ◽  
Huixiang Zhu ◽  
Eric Luu ◽  
Guangyao Huang ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
22Q11.2 Deletion Syndrome ◽  
Cell Junctions ◽  
Brain Barrier ◽  
Endothelial Glycocalyx ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Solute Permeability ◽  
Blood Brain

The blood–brain barrier (BBB) is important in the normal functioning of the central nervous system. An altered BBB has been described in various neuropsychiatric disorders, including schizophrenia. However, the cellular and molecular mechanisms of such alterations remain unclear. Here, we investigate if BBB integrity is compromised in 22q11.2 deletion syndrome (also called DiGeorge syndrome), which is one of the validated genetic risk factors for schizophrenia. We utilized a set of human brain microvascular endothelial cells (HBMECs) derived from the induced pluripotent stem cell (iPSC) lines of patients with 22q11.2-deletion-syndrome-associated schizophrenia. We found that the solute permeability of the BBB formed from patient HBMECs increases by ~1.3–1.4-fold, while the trans-endothelial electrical resistance decreases to ~62% of the control values. Correspondingly, tight junction proteins and the endothelial glycocalyx that determine the integrity of the BBB are significantly disrupted. A transcriptome study also suggests that the transcriptional network related to the cell–cell junctions in the compromised BBB is substantially altered. An enrichment analysis further suggests that the genes within the altered gene expression network also contribute to neurodevelopmental disorders. Our findings suggest that neurovascular coupling can be targeted in developing novel therapeutical strategies for the treatment of 22q11.2 deletion syndrome.

scholarly journals Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

2019 ◽  
Author(s):  
Alexis M. Crockett ◽  
Sean K. Ryan ◽  
Adriana Hernandez Vasquez ◽  
Caroline Canning ◽  
Nickole Kanyuch ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
22Q11.2 Deletion Syndrome ◽  
Immune Privilege ◽  
Brain Barrier ◽  
Intercellular Adhesion Molecule ◽  
Deletion Syndrome ◽  
Intercellular Adhesion Molecule 1 ◽  
Blood Brain ◽  
Induced Pluripotent ◽  
Immune Imbalance

ABSTRACTNeuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ). As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease.

scholarly journals Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

2008 ◽  
Vol 6 (3) ◽  
pp. 179-192 ◽  
Author(s):  
Svetlana Stamatovic ◽  
Richard Keep ◽  
Anuska Andjelkovic
Keyword(s):  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Junctions ◽  
Brain Barrier ◽  
Brain Endothelial Cell ◽  
Blood Brain ◽  
Cell Cell

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

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.

scholarly journals Glycocalyx degradation leads to blood–brain barrier dysfunction and brain edema after asphyxia cardiac arrest in rats

2017 ◽  
Vol 38 (11) ◽  
pp. 1979-1992 ◽  
Author(s):  
Jiajia Zhu ◽  
Xing Li ◽  
Jia Yin ◽  
Yafang Hu ◽  
Yong Gu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Survival Rate ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Neurologic Outcome ◽  
Endothelial Glycocalyx ◽  
Inflammatory Factors ◽  
Blood Brain ◽  
Bbb Permeability

The role of glycocalyx in blood–brain barrier (BBB) integrity and brain damage is poorly understood. Our study aimed to investigate the impacts of endothelial glycocalyx on BBB function in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Male Sprague-Dawley rats subjected to 8-min asphyxia CA/CPR. Compared to controls, glycocalyx was mildly injured by CA, severely disrupted by hyaluronidase (HAase) with CA, and mitigated by hydrocortisone (HC) with CA. More importantly, the disruption of glycocalyx caused by HAase treatment was associated with higher BBB permeability and aggravated brain edema at 24 h after return of spontaneous circulation, as well as lower survival rate and poorer neurologic outcome at seventh day. Reversely, less degradation of glycocalyx by HC treatment was accompanied by higher seven-day survival rate and better neurologic outcome. Mechanistically, HAase treatment further increased CA/CPR-induced activation of glia cells and expression of inflammatory factors, whereas HC decreased them in the brain cortex and hippocampus. Glycocalyx degradation results in BBB leakage, brain edema, and deteriorates neurologic outcome after asphyxia CA/CPR in rats. Preservation of glycocalyx by HC could improve neurologic outcome and reduce BBB permeability, apparently through reduced gene transcription-protein synthesis and inflammation.

scholarly journals Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

2021 ◽  
Vol 22 (18) ◽  
pp. 10045
Author(s):  
Phuong Thao Do ◽  
Chung-Che Wu ◽  
Yung-Hsiao Chiang ◽  
Chaur-Jong Hu ◽  
Kai-Yun Chen
Keyword(s):  
Stem Cells ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Brain Regions ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Pathophysiological Mechanism ◽  
Cell Based Therapy ◽  
Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

scholarly journals Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

2020 ◽  
Vol 13 (626) ◽  
pp. eaay5686 ◽  
Author(s):  
Feifei Ma ◽  
Ping Sun ◽  
Xuejing Zhang ◽  
Milton H. Hamblin ◽  
Ke-Jie Yin
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Protein Abundance ◽  
Barrier Dysfunction ◽  
Small Noncoding Rnas ◽  
Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

scholarly journals Fgfbp1 promotes blood-brain barrier development by regulating collagen IV deposition and maintaining Wnt/β-catenin signaling

Development ◽  
2020 ◽  
Vol 147 (16) ◽  
pp. dev185140
Author(s):  
Azzurra Cottarelli ◽  
Monica Corada ◽  
Galina V. Beznoussenko ◽  
Alexander A. Mironov ◽  
Maria A. Globisch ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Blood Brain Barrier ◽  
Collagen Iv ◽  
Cell Junctions ◽  
Brain Barrier ◽  
Extracellular Matrix Protein ◽  
Genetic Ablation ◽  
Vascular Basement Membrane ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells

ABSTRACTCentral nervous system (CNS) blood vessels contain a functional blood-brain barrier (BBB) that is necessary for neuronal survival and activity. Although Wnt/β-catenin signaling is essential for BBB development, its downstream targets within the neurovasculature remain poorly understood. To identify targets of Wnt/β-catenin signaling underlying BBB maturation, we performed a microarray analysis that identified Fgfbp1 as a novel Wnt/β-catenin-regulated gene in mouse brain endothelial cells (mBECs). Fgfbp1 is expressed in the CNS endothelium and secreted into the vascular basement membrane during BBB formation. Endothelial genetic ablation of Fgfbp1 results in transient hypervascularization but delays BBB maturation in specific CNS regions, as evidenced by both upregulation of Plvap and increased tracer leakage across the neurovasculature due to reduced Wnt/β-catenin activity. In addition, collagen IV deposition in the vascular basement membrane is reduced in mutant mice, leading to defective endothelial cell-pericyte interactions. Fgfbp1 is required cell-autonomously in mBECs to concentrate Wnt ligands near cell junctions and promote maturation of their barrier properties in vitro. Thus, Fgfbp1 is a crucial extracellular matrix protein during BBB maturation that regulates cell-cell interactions and Wnt/β-catenin activity.

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