PMID- 36545654
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221223
IS  - 1662-5102 (Print)
IS  - 1662-5102 (Electronic)
IS  - 1662-5102 (Linking)
VI  - 16
DP  - 2022
TI  - A human-derived neurovascular unit in vitro model to study the effects of 
      cellular cross-talk and soluble factors on barrier integrity.
PG  - 1065193
LID - 10.3389/fncel.2022.1065193 [doi]
LID - 1065193
AB  - The blood-brain barrier (BBB) restricts paracellular and transcellular diffusion 
      of compounds and is part of a dynamic multicellular structure known as the 
      "neurovascular unit" (NVU), which strictly regulates the brain homeostasis and 
      microenvironment. Several neuropathological conditions (e.g., Parkinson's disease 
      and Alzheimer's disease), are associated with BBB impairment yet the exact 
      underlying pathophysiological mechanisms remain unclear. In total, 90% of drugs 
      that pass animal testing fail human clinical trials, in part due to inter-species 
      discrepancies. Thus, in vitro human-based models of the NVU are essential to 
      better understand BBB mechanisms; connecting its dysfunction to neuropathological 
      conditions for more effective and improved therapeutic treatments. Herein, we 
      developed a biomimetic tri-culture NVU in vitro model consisting of 3 
      human-derived cell lines: human cerebral micro-vascular endothelial cells 
      (hCMEC/D3), human 1321N1 (astrocyte) cells, and human SH-SY5Y neuroblastoma 
      cells. The cells were grown in Transwell hanging inserts in a variety of 
      configurations and the optimal setup was found to be the comprehensive 
      tri-culture model, where endothelial cells express typical markers of the BBB and 
      contribute to enhancing neural cell viability and neurite outgrowth. The 
      tri-culture configuration was found to exhibit the highest transendothelial 
      electrical resistance (TEER), suggesting that the cross-talk between astrocytes 
      and neurons provides an important contribution to barrier integrity. Lastly, the 
      model was validated upon exposure to several soluble factors [e.g., 
      Lipopolysaccharides (LPS), sodium butyrate (NaB), and retinoic acid (RA)] known 
      to affect BBB permeability and integrity. This in vitro biological model can be 
      considered as a highly biomimetic recapitulation of the human NVU aiming to 
      unravel brain pathophysiology mechanisms as well as improve testing and delivery 
      of therapeutics.
CI  - Copyright (c) 2022 Barberio, Withers, Mishra, Couraud, Romero, Weksler and Owens.
FAU - Barberio, Chiara
AU  - Barberio C
AD  - Department of Chemical Engineering and Biotechnology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Withers, Aimee
AU  - Withers A
AD  - Department of Chemical Engineering and Biotechnology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Mishra, Yash
AU  - Mishra Y
AD  - Department of Chemical Engineering and Biotechnology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Couraud, Pierre-Olivier
AU  - Couraud PO
AD  - Institut Cochin, Centre National de la Recherche Scientifique UMR 8104, Institut 
      National de la Sante et de la Recherche Medicale (INSERM) U567, Universite Rene 
      Descartes, Paris, France.
FAU - Romero, Ignacio A
AU  - Romero IA
AD  - Department of Biological Sciences, The Open University, Milton Keynes, United 
      Kingdom.
FAU - Weksler, Babette
AU  - Weksler B
AD  - Department of Medicine, Weill Medical College of Cornell University, New York, 
      NY, United States.
FAU - Owens, Roisin M
AU  - Owens RM
AD  - Department of Chemical Engineering and Biotechnology, University of Cambridge, 
      Cambridge, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20221201
PL  - Switzerland
TA  - Front Cell Neurosci
JT  - Frontiers in cellular neuroscience
JID - 101477935
PMC - PMC9762047
OTO - NOTNLM
OT  - Transwell
OT  - blood-brain barrier (BBB)
OT  - human immortalized cell lines
OT  - in vitro
OT  - neurovascular unit (NVU) model
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- 2022/12/23 06:00
MHDA- 2022/12/23 06:01
PMCR- 2022/01/01
CRDT- 2022/12/22 02:43
PHST- 2022/10/09 00:00 [received]
PHST- 2022/11/15 00:00 [accepted]
PHST- 2022/12/22 02:43 [entrez]
PHST- 2022/12/23 06:00 [pubmed]
PHST- 2022/12/23 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fncel.2022.1065193 [doi]
PST - epublish
SO  - Front Cell Neurosci. 2022 Dec 1;16:1065193. doi: 10.3389/fncel.2022.1065193. 
      eCollection 2022.