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Anatomia e Histologia, 26 de Novembro
Seminário I
Stem Cell-Based Human Blood–Brain Barrier
Models for Drug Discovery and Delivery
T R E N D S I N B I OT E C H N O LO GY, M AY 2 0 1 6
S. Aday, R. Cecchelli, D. Hallier-Vanuxeem, M.P. Dehouck, and L. Ferreira
Carolina Faria–86762 Catarina Martins-86766 Gonçalo Salvador–86770 Margarida Costa–86788 Maria Salgueiro–86794 Nuno Oliveira–86799 Teresa Marcelino-86795
Expression and functionalities of transporters
Ability to cross the Blood-Brain Barrier
Neuropharmaceuticals development
BBB Structure
Differences among species
Permeability
LC-MS*
Analytical chemistry technique that combines the physical
separation capabilities of liquid chromatography with the mass
*Liquid chromatography–
mass spectrometry
analysis capabilities of mass spectrometry
Transporters
MRP4
LAT1
Protects the brain from pharmaceutical
substances
Aminoacid transporter – the low expression of LAT1 makes the
transportation of aminoacids to the brain inefficient
P-glycoprotein
Responsible for the active back-transport (expulsion) of
substances to the blood
PET Scan
A positron emission tomography scan is a
type of imaging test. It uses a radioactive
substance called tracer
Both PET Scan and LC-MS reveal that P-gp are less eficient in
human than in roedents.
paracelular
Humans
Rodents
Claudin-1

X
Claudin-2


In vitro Blood-Brain Barrier models, based on
stem-cells
Difficulty on getting human tissue;
Lost of human brain endotelial cells fenotipes;
Low values of TEER*;
Missing important tigh junctions.
*TEER: trans endothelial electrical
resistance
Blood-Brain Barrier
Models
Human
pluripotents
stem-cells
Human
multipotents
stem-cells
Human
pluripotent
stem-cells
Human pluripotent stem-cells
TEER
In Vivo
>1000Ω.cm²
With astrocytes
1450 +/- 140Ω.cm ²
Monoculture
222 +/- Ω.cm²
Co-cultured with
differentiated human
neural progenitor cells
> 5000 Ω.cm²
Measures the integrity of tight junction dynamics in cell culture
models thus allowing the measurement of the permeability of the
model
Human multipotent stem-cells
endothelial progenitor cells from
the cord blood (MNCs)
collagen type I
astrocytes
hematopoietic stem/progenitor
cells from the cord blood (CD34+)
pericytes
Experimental models of the
Blood-Brain Barrier
Studying Blood-Brain Barrier
permeability to drugs
Predicting the pharmacological
activities of these drugs in the
brain
Conclusions and Future
Futures studies
Approaches
• Modification of existing drugs
• Development of nanoformulations
• Use of molecular trojan horses
Bibliography
https://plataforma.elearning.ulisboa.pt/file.php/6977/Seminarios/PDF_2016_2017/PIIS016
7779916000044.pdf
https://www.ncbi.nlm.nih.gov/pubmed/10837715
https://www.ncbi.nlm.nih.gov/pubmed/25586998
https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiologytextbook/integumentary-system-5/cell-junctions-1359/tight-junctions-1360-7747/
http://www.discoverymedicine.com/William-M-Pardridge/2009/07/27/molecular-trojanhorses-for-blood-brain-barrier-drug-delivery/
https://www.jic.ac.uk/services/metabolomics/topics/lcms/why.htm