PMID- 37818458
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231012
IS  - 1662-5099 (Print)
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 16
DP  - 2023
TI  - Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T 
      cell migration under neuroinflammatory conditions.
PG  - 1250123
LID - 10.3389/fnmol.2023.1250123 [doi]
LID - 1250123
AB  - The blood-brain barrier (BBB) is a highly selective barrier that ensures a 
      homeostatic environment for the central nervous system (CNS). BBB dysfunction, 
      inflammation, and immune cell infiltration are hallmarks of many CNS disorders, 
      including multiple sclerosis and stroke. Physiologically relevant human in vitro 
      models of the BBB are essential to improve our understanding of its function in 
      health and disease, identify novel drug targets, and assess potential new 
      therapies. We present a BBB-on-a-chip model comprising human brain microvascular 
      endothelial cells (HBMECs) cultured in a microfluidic platform that allows 
      parallel culture of 40 chips. In each chip, a perfused HBMEC vessel was grown 
      against an extracellular matrix gel in a membrane-free manner. BBBs-on-chips were 
      exposed to varying concentrations of pro-inflammatory cytokines tumor necrosis 
      factor alpha (TNFalpha) and interleukin-1 beta (IL-1beta) to mimic inflammation. The 
      effect of the inflammatory conditions was studied by assessing the BBBs-on-chips' 
      barrier function, cell morphology, and expression of cell adhesion molecules. 
      Primary human T cells were perfused through the lumen of the BBBs-on-chips to 
      study T cell adhesion, extravasation, and migration. Under inflammatory 
      conditions, the BBBs-on-chips showed decreased trans-endothelial electrical 
      resistance (TEER), increased permeability to sodium fluorescein, and aberrant 
      cell morphology in a concentration-dependent manner. Moreover, we observed 
      increased expression of cell adhesion molecules and concomitant monocyte 
      adhesion. T cells extravasated from the inflamed blood vessels and migrated 
      towards a C-X-C Motif Chemokine Ligand 12 (CXCL12) gradient. T cell adhesion was 
      significantly reduced and a trend towards decreased migration was observed in 
      presence of Natalizumab, an antibody drug that blocks very late antigen-4 (VLA-4) 
      and is used in the treatment of multiple sclerosis. In conclusion, we demonstrate 
      a high-throughput microfluidic model of the human BBB that can be used to model 
      neuroinflammation and assess anti-inflammatory and barrier-restoring 
      interventions to fight neurological disorders.
CI  - Copyright (c) 2023 Nair, Groenendijk, Overdevest, Fowke, Annida, Mocellin, de Vries 
      and Wevers.
FAU - Nair, Arya Lekshmi
AU  - Nair AL
AD  - MIMETAS BV, Oegstgeest, Netherlands.
AD  - Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience - 
      Neuroinfection and Neuroinflammation, Amsterdam, Netherlands.
FAU - Groenendijk, Linda
AU  - Groenendijk L
AD  - MIMETAS BV, Oegstgeest, Netherlands.
FAU - Overdevest, Roos
AU  - Overdevest R
AD  - MIMETAS BV, Oegstgeest, Netherlands.
FAU - Fowke, Tania M
AU  - Fowke TM
AD  - MIMETAS BV, Oegstgeest, Netherlands.
FAU - Annida, Rumaisha
AU  - Annida R
AD  - MIMETAS BV, Oegstgeest, Netherlands.
FAU - Mocellin, Orsola
AU  - Mocellin O
AD  - MIMETAS BV, Oegstgeest, Netherlands.
FAU - de Vries, Helga E
AU  - de Vries HE
AD  - Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience - 
      Neuroinfection and Neuroinflammation, Amsterdam, Netherlands.
FAU - Wevers, Nienke R
AU  - Wevers NR
AD  - MIMETAS BV, Oegstgeest, Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20230925
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC10561300
OTO - NOTNLM
OT  - BBB-on-a-chip
OT  - blood-brain barrier
OT  - neuroinflammation
OT  - organ-on-a-chip
OT  - transendothelial migration
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/10/11 06:45
MHDA- 2023/10/11 06:46
PMCR- 2023/01/01
CRDT- 2023/10/11 04:01
PHST- 2023/06/29 00:00 [received]
PHST- 2023/09/06 00:00 [accepted]
PHST- 2023/10/11 06:46 [medline]
PHST- 2023/10/11 06:45 [pubmed]
PHST- 2023/10/11 04:01 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2023.1250123 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2023 Sep 25;16:1250123. doi: 10.3389/fnmol.2023.1250123. 
      eCollection 2023.