In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals
Abstract
:1. Background
2. Structure and Physio-Anatomical Features of the BCSFB
2.1. Tight Junctions
2.2. Specific Markers and Receptors
2.3. Transporters and Ion Channels
2.4. Xeno- and Endobiotic Efflux Systems
3. Survey of Available Platforms
3.1. Static Monolayer Cultures Using Bicameral Systems
3.2. Co-Culture Models
3.3. 3D Cultures and Organoids
3.3.1. 3D Explants and Cultured Cells in a Scaffold System
3.3.2. Organoids and Self-Organized 3D Models
3.3.3. Three-Dimensional Bioprinting Strategies
3.4. Dynamic Models and Microfluidic Platforms
4. Survey of Available Cells
4.1. Cerebral Originating Cells
4.2. Noncerebral-Based Cells (Surrogate Models)
5. Models Validation Criteria
5.1. Barrier Morphology
5.2. Barrier Properties
5.3. Exogenous Tracer Permeability
5.4. Functional Junctional Proteins and Transporters
5.5. Factors Critical to Cell Selection and Culture Conditions
6. Applications in (Neuro)Therapeutics Development and Research
6.1. Permeability Screenings and Studies
6.2. Transport Mechanisms Studies and (Targeted)Drug Delivery
Drug Delivery Employing Transport Mechanisms at the BCSFB
6.3. Metabolites/Xenobiotics Transport(er) Regulation
6.4. In Vitro Molecular Verification of Pharmacological Activity
6.5. (Neuro)Toxicological Studies
6.6. Pharmacological Interventions at the BCSFB
6.7. The BCSFB and Choroid Plexus as a Drug Target in Various Diseases
7. Conclusions and Future Outlook
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
2D | two dimensional |
3D | three dimensional |
5-HT | 5-hydroxytryptamine |
ABC | ATP-binding cassette |
ADME | absorption, distribution, metabolism, excretion |
ANP | atrial natriuretic peptide |
ATPase | adenosine triphosphatase |
AVP | arginine vasopressin |
BBB | blood–brain barrier |
BCRP | breast cancer resistance protein |
BCSFB | blood–cerebrospinal fluid barrier |
CDE | clathrin-dependent endocytosis |
CIE | clathrin-independent endocytosis |
CMT | carrier-mediated transport |
CNS | central nervous system |
CP | choroid plexus |
CSF | cerebrospinal fluid |
EHs | epoxide hydrolases |
ESCs | embryonic stem cells |
FITC | fluorescein isothiocyanate |
FMOs | flavin-containing monooxygenases |
FPRL1 | formylpeptide receptor-like 1 |
GSTs | glutathione S-transferases |
HTS | high throughput screening |
IGF | insulin-like growth factor |
IGFR | insulin-like growth factor receptor |
iPSCs | induced pluripotent stem cells |
IR | insulin receptor |
ISF | interstitial fluid |
JAMs | junctional adhesion molecules |
LDLR | low-density lipoprotein receptor |
LLC-PK1 | Lilly laboratories culture-porcine kidney 1 |
LRP | LDLR-related protein |
MAGUKs | membrane-associated guanylate kinase-like homologues |
MDCK | Madin-Darby canine kidney |
MDR | multidrug resistance protein |
MMP | matrix metalloproteinase |
MPS | Mucopolysaccharidosis |
MRP | multidrug resistance-associated protein |
NPs | Nanoparticles |
NHE | Na+-H+ exchanger |
PC | polycarbonate |
PCPEC | porcine choroid plexus epithelial cells |
PET | polyethylene terephthalate |
P-gp | P-glycoprotein |
PIOs | 2-phenoxy-indan-1-one |
PTFE | polytetrafluoroethylene |
QAR | quantitative autoradiographic |
RMT | receptor-mediated transcytosis |
RRCK | Ralph Russ canine kidney |
SAR | structure–activity relationships |
SLC | solute carrier |
TAMARA | tetramethylrhodamine |
TEER | transepithelial electrical resistance |
TEM | transmission electron microscopy |
Tf | transferrin |
TfR | transferrin receptor |
TJ | tight junction |
TTR | transthyretin |
UGTs | UDP-glucuronosyltransferases |
ZO | Zonula occludens |
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Family | Transporter Function | Members Present on Choroid Plexus Epithelial Cells (Also-Known-as) |
---|---|---|
SLC1 | High-affinity glutamate and neutral amino acids | SLC1A3, SLC1A4, SLC1A5 (ASCT2) |
SLC2 | Facultative GLUT transporters | SLC2A1 (GLUT1), SLC2A6, SLC2A10, SLC2A12 |
SLC4 | Bicarbonate transporters (anion exchanger) | SLC4A1, SLC4A2 (AE2), SLC4A4, SLC4A5 (NBC4/NBCe2), SLC4A8, SLC4A10, SLC4A11 |
SLC5 | Sodium glucose cotransporters | SLC5A1, SLC5A5, SLC5A6 |
SLC6 | Sodium- and chloride-dependent neurotransmitter transporters | SLC6A4, SLC6A6, SLC6A8 (Crt), SLC6A9, SLC6A11, SLC6A13, SLC6A14, SLC6A15, SLC6A17, SLC6A20A, SLC6A20B |
SLC7 | Cationic amino acid transporter/glycoprotein- associated | SLC7A1, SLC7A2, SLC7A5 (LAT1), SLC7A6 (LAT2), SLC7A7, SLC7A10 |
SLC8 | Na+/Ca2+ exchangers | SLC8A1 |
SLC9 | Na+/H+ exchangers (antiporter) | SLC9A1 (NHE1), SLC9A2, SLC9A6 (NHE6), SLC9A7, SLC9A8, SLC9A9 |
SLC10 | Sodium/bile acid co-transporter family | SLC10A3 |
SLC11 | Proton coupled metal ion transporters | SLC11A2 |
SLC12 | Electroneutral cation-coupled Cl− cotransporters | SLC12A2 (NKCC1), SLC12A4 (KCC1) |
SLC13 | Human Na+-sulfate/carboxylate cotransporters | SLC13A4, SLC13A5 |
SLC14 | Urea transporters | SLC14A2 |
SLC15 | Proton oligopeptide co-transporters | SLC15A2 (PEPT2) |
SLC16 | Monocarboxylate/monocarboxylic acid transporter family | SLC16A3, SLC16A4, SLC16A6, SLC16A8, SLC16A9, SLC16A10 |
SLC17 | Vesicular glutamate transporters | SLC17A6 |
SLC20 | Type III Na+-phosphate cotransporters | SLC20A1, SLC20A2 |
SLC21/SLCO | Organic anion transporters | SLCO1A5 (OATP1A5), SLCO 1C1, SLCO 2A1 (Pgt), SLCO5A1 |
SLC22 | Organic cation/anion/zwitterion transporters | SLC22A5 (OCTN2), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A17, SLC22A18, SLC22A21, SLC22A23 |
SLC23 | Na+-dependent ascorbic acid transporters | SLC23A2 |
SLC24 | Na+/(Ca2+/K+) exchangers | SLC24A3, SLC24A4, SLC24A5 |
SLC25 | Mitochondrial carriers | SLC25A1, SLC25A10, SLC25A12, SLC25A14, SLC25A16, SLC25A17, SLC25A18, SLC25A21, SLC25A22, SLC25A26, SLC25A27, SLC25A30, SLC25A32, SLC25A33, SLC25A35, SLC25A37, SLC25A38, SLC25A39, SLC25A45 |
SLC26 | Multifunctional anion exchangers | SLC26A2, SLC26A7 |
SLC27 | Fatty acid transporters | SLC27A1, SLC27A2, SLC27A3 |
SLC28 | Na+-coupled nucleoside transporters | SLC28A3 |
SLC29 | Facilitative nucleoside transporters | SLC29A2, SLC29A4 (PMAT) |
SLC30 | Zn2+ efflux transporters | SLC30A3, SLC30A4, SLC30A5, SLC30A6, SLC30A9, SLC30A10 |
SLC31 | Cu2+ transporters | SLC31A1, SLC31A2 |
SLC33 | Acetyl-CoA transporters | SLC33A1 |
SLC35 | Nucleoside-sugar transporters | SLC35A1, SLC35A4, SLC35A5, SLC35D2, SLC35E2, SLC35E4, SLC35F1, SLC35F2, SLC35F3, SLC35F5 |
SLC37 | Sugar-phosphate/phosphate exchangers | SLC37A1 (G3PP), SLC37A2 |
SLC38 | Amino acid transporter | SLC38A1, SLC38A3, SLC38A4, SLC38A5, SLC38A11 |
SLC39 | Metal ion transporters | SLC39A4, SLC39A8, SLC39A10, SLC39A11, SLC39A12, SLC39A14 |
SLC40 | Basolateral Fe2+ transporters | SLC40A1 |
SLC41 | MgtE-like magnesium transporters | SLC41A1, SLC41A2 |
SLC43 | Na+-independent, system-L-like amino acid transporters | SLC43A1, SLC43A2 |
SLC44 | Choline-like transporters | SLC44A3 |
SLC45 | Putative sugar transporters | SLC45A4 |
SLC46 | Folate transporters | SLC46A1, SLC46A3 |
SLC48 | Heme transporters | SLC48A1 |
SLC50 | Sugar efflux transporters | SLC50A1 |
Model and Its Description | Applications | Advantages | Disadvantages | Throughput |
---|---|---|---|---|
2D static bicameral devices (cell culture inserts) or compartmentalized monocultures. |
|
|
| Moderate (offers HTS capabilities). |
Co-culture models. | Study drug permeability. |
|
| Moderate. |
3D and organoids. |
|
|
| Low to medium. |
Dynamic models (microfluidic or organ-on-a-chip platforms). |
|
|
| Low to medium. |
Cell Types | Main Advantages and Disadvantages | Origin | Cells | Species Source |
---|---|---|---|---|
Primary cell cultures |
| Cerebral | Pig primary cells, PCPEC | Pig |
Mouse primary cells | Mouse | |||
Rat primary cells | Rat | |||
Bovine primary cells | Cow | |||
Ovine primary cells | Sheep | |||
Rabbit primary cells | Rabbit | |||
HCPEpiC | Human | |||
Non-cerebral | No Reports | |||
Immortalized and continuous cell lines |
| Cerebral | Z310 | Rat |
TR-CSFB | Rat | |||
ECPC3 | Mouse | |||
ECPC4 | Mouse | |||
SV11 | Mouse | |||
PCP-R | Pig | |||
HIBCPP | Human | |||
CPC-2 | Human | |||
iHCPEnC | Human | |||
Non-cerebral | MDCK | Dog | ||
MDCK-MDR1 | Dog | |||
RRCK | Dog | |||
Caco-2 | Human | |||
LLC-PK1 | Pig |
Marker | Size | ||
---|---|---|---|
Molecular Weight (Da) | Approximate Hydrodynamic Radius (nm) | ||
Markers of Protein/Macromolecules Permeability | |||
Dyes | Evans blue | 960 | NR 1 |
Trypan blue | 961 | NR | |
Fluorescent tracers | FITC-dextran 150 kDa | 150,000 | 9.0 ± 0.6 |
FITC-dextran 70 kDa | 70,000 | 6 | |
FITC-dextran 40 kDa | 40,000 | 4.5 | |
FITC-albumin | 67,000 | 5.4 ± 0.1 | |
Horseradish peroxidase | 40,000 | 5–6 | |
Microperoxidase | 1900 | 3.0 | |
Radiolabeled Compounds | [125I]-albumin | ~69,000 | 3.5 |
[14C]-dextran 70 kDa | ~70,000 | 6 | |
Markers of Solute and Ion Permeability | |||
Ionic Lanthanum | 138.9 | 0.12 | |
Sodium Fluorescein | 376 | 0.45 | |
Lucifer Yellow | 457 | 0.42 | |
Biotin ethylenediamine | 286 | NR | |
FITC-dextran 3kDa | 3000 | 1.4 | |
Radiolabeled Compounds | [14C]-α-Aminoisobutyric acid | 103 | NR |
[14C]-Sucrose | 342 | 0.46 | |
[3H]-mannitol | 182 | 0.36 | |
[14C]-Methotrexate | 455 | NR | |
[14C]-Inulin | 5000 | 1.3 |
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Dabbagh, F.; Schroten, H.; Schwerk, C. In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals. Pharmaceutics 2022, 14, 1729. https://doi.org/10.3390/pharmaceutics14081729
Dabbagh F, Schroten H, Schwerk C. In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals. Pharmaceutics. 2022; 14(8):1729. https://doi.org/10.3390/pharmaceutics14081729
Chicago/Turabian StyleDabbagh, Fatemeh, Horst Schroten, and Christian Schwerk. 2022. "In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals" Pharmaceutics 14, no. 8: 1729. https://doi.org/10.3390/pharmaceutics14081729