Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5)

Research output: Contribution to journalJournal articlepeer-review

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Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5). / Goldeman, C.; Andersen, M.; Al-Robai, A.; Buchholtz, T.; Svane, N.; Ozgür, B; Holst, B.; Shusta, E.; Hall, V. J.; Saaby, L.; Hyttel, P.; Brodin, B.

In: European Journal of Pharmaceutical Sciences, Vol. 156, 105577, 2021.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Goldeman, C, Andersen, M, Al-Robai, A, Buchholtz, T, Svane, N, Ozgür, B, Holst, B, Shusta, E, Hall, VJ, Saaby, L, Hyttel, P & Brodin, B 2021, 'Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5)', European Journal of Pharmaceutical Sciences, vol. 156, 105577. https://doi.org/10.1016/j.ejps.2020.105577

APA

Goldeman, C., Andersen, M., Al-Robai, A., Buchholtz, T., Svane, N., Ozgür, B., Holst, B., Shusta, E., Hall, V. J., Saaby, L., Hyttel, P., & Brodin, B. (2021). Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5). European Journal of Pharmaceutical Sciences, 156, [105577]. https://doi.org/10.1016/j.ejps.2020.105577

Vancouver

Goldeman C, Andersen M, Al-Robai A, Buchholtz T, Svane N, Ozgür B et al. Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5). European Journal of Pharmaceutical Sciences. 2021;156. 105577. https://doi.org/10.1016/j.ejps.2020.105577

Author

Goldeman, C. ; Andersen, M. ; Al-Robai, A. ; Buchholtz, T. ; Svane, N. ; Ozgür, B ; Holst, B. ; Shusta, E. ; Hall, V. J. ; Saaby, L. ; Hyttel, P. ; Brodin, B. / Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5). In: European Journal of Pharmaceutical Sciences. 2021 ; Vol. 156.

Bibtex

@article{b7e4b797a2f34008bf5e9a291cfff913,
title = "Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5)",
abstract = "The barrier properties of the brain capillary endothelium, the blood-brain barrier (BBB) restricts uptake of most small and all large molecule drug compounds to the CNS. There is a need for predictive human in vitro models of the BBB to enable studies of brain drug delivery. Here, we investigated whether human induced pluripotent stem cell (hiPSC) line (BIONi010-C) could be differentiated to brain capillary endothelial- like cells (BCEC) and evaluated their potential use in drug delivery studies. BIONi010-C hIPSCs were differentiated according to established protocols. BCEC monolayers displayed transendothelial electrical resistance (TEER) values of 5,829±354 Ω∙cm2, a Papp,mannitol of 1.09±0.15 ∙ 10-6 cm∙s-1 and a Papp,diazepam of 85.7±5.9 ∙ 10-6 cm ∙s-1. The Pdiazepam/Pmannitol ratio of ∼80, indicated a large dynamic passive permeability range. Monolayers maintained their integrity after medium exchange. Claudin-5, Occludin, Zonulae Occludens 1 and VE-Cadherin were expressed at the cell-cell contact zones. Efflux transporters were present at the mRNA level, but functional efflux of substrates was not detected. Transferrin-receptor (TFR), Low density lipoprotein receptor-related protein 1 (LRP1) and Basigin receptors were expressed at the mRNA-level. The presence and localization of TFR and LRP1 were verified at the protein level. A wide range of BBB-expressed solute carriers (SLC's) were detected at the mRNA level. The presence and localization of SLC transporters GLUT1 and LAT1 was verified at the protein level. Functional studies revealed transport of the LAT1 substrate [3H]-L-Leucine and the LRP1 substrate angiopep-2. In conclusion, we have demonstrated that BIONi010-C-derived BCEC monolayers exhibited, BBB properties including barrier tightness and integrity, a high dynamic range, expression of some of the BBB receptor and transporter expression, as well as functional transport of LAT1 and LRP1 substrates. This suggests that BIONi010-C-derived BCEC monolayers may be useful for studying the roles of LAT-1 and LRP1 in brain drug delivery.",
author = "C. Goldeman and M. Andersen and A. Al-Robai and T. Buchholtz and N. Svane and B Ozg{\"u}r and B. Holst and E. Shusta and Hall, {V. J.} and L. Saaby and P. Hyttel and B. Brodin",
note = "Copyright {\textcopyright} 2020. Published by Elsevier B.V.",
year = "2021",
doi = "10.1016/j.ejps.2020.105577",
language = "English",
volume = "156",
journal = "Norvegica Pharmaceutica Acta",
issn = "0928-0987",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5)

AU - Goldeman, C.

AU - Andersen, M.

AU - Al-Robai, A.

AU - Buchholtz, T.

AU - Svane, N.

AU - Ozgür, B

AU - Holst, B.

AU - Shusta, E.

AU - Hall, V. J.

AU - Saaby, L.

AU - Hyttel, P.

AU - Brodin, B.

N1 - Copyright © 2020. Published by Elsevier B.V.

PY - 2021

Y1 - 2021

N2 - The barrier properties of the brain capillary endothelium, the blood-brain barrier (BBB) restricts uptake of most small and all large molecule drug compounds to the CNS. There is a need for predictive human in vitro models of the BBB to enable studies of brain drug delivery. Here, we investigated whether human induced pluripotent stem cell (hiPSC) line (BIONi010-C) could be differentiated to brain capillary endothelial- like cells (BCEC) and evaluated their potential use in drug delivery studies. BIONi010-C hIPSCs were differentiated according to established protocols. BCEC monolayers displayed transendothelial electrical resistance (TEER) values of 5,829±354 Ω∙cm2, a Papp,mannitol of 1.09±0.15 ∙ 10-6 cm∙s-1 and a Papp,diazepam of 85.7±5.9 ∙ 10-6 cm ∙s-1. The Pdiazepam/Pmannitol ratio of ∼80, indicated a large dynamic passive permeability range. Monolayers maintained their integrity after medium exchange. Claudin-5, Occludin, Zonulae Occludens 1 and VE-Cadherin were expressed at the cell-cell contact zones. Efflux transporters were present at the mRNA level, but functional efflux of substrates was not detected. Transferrin-receptor (TFR), Low density lipoprotein receptor-related protein 1 (LRP1) and Basigin receptors were expressed at the mRNA-level. The presence and localization of TFR and LRP1 were verified at the protein level. A wide range of BBB-expressed solute carriers (SLC's) were detected at the mRNA level. The presence and localization of SLC transporters GLUT1 and LAT1 was verified at the protein level. Functional studies revealed transport of the LAT1 substrate [3H]-L-Leucine and the LRP1 substrate angiopep-2. In conclusion, we have demonstrated that BIONi010-C-derived BCEC monolayers exhibited, BBB properties including barrier tightness and integrity, a high dynamic range, expression of some of the BBB receptor and transporter expression, as well as functional transport of LAT1 and LRP1 substrates. This suggests that BIONi010-C-derived BCEC monolayers may be useful for studying the roles of LAT-1 and LRP1 in brain drug delivery.

AB - The barrier properties of the brain capillary endothelium, the blood-brain barrier (BBB) restricts uptake of most small and all large molecule drug compounds to the CNS. There is a need for predictive human in vitro models of the BBB to enable studies of brain drug delivery. Here, we investigated whether human induced pluripotent stem cell (hiPSC) line (BIONi010-C) could be differentiated to brain capillary endothelial- like cells (BCEC) and evaluated their potential use in drug delivery studies. BIONi010-C hIPSCs were differentiated according to established protocols. BCEC monolayers displayed transendothelial electrical resistance (TEER) values of 5,829±354 Ω∙cm2, a Papp,mannitol of 1.09±0.15 ∙ 10-6 cm∙s-1 and a Papp,diazepam of 85.7±5.9 ∙ 10-6 cm ∙s-1. The Pdiazepam/Pmannitol ratio of ∼80, indicated a large dynamic passive permeability range. Monolayers maintained their integrity after medium exchange. Claudin-5, Occludin, Zonulae Occludens 1 and VE-Cadherin were expressed at the cell-cell contact zones. Efflux transporters were present at the mRNA level, but functional efflux of substrates was not detected. Transferrin-receptor (TFR), Low density lipoprotein receptor-related protein 1 (LRP1) and Basigin receptors were expressed at the mRNA-level. The presence and localization of TFR and LRP1 were verified at the protein level. A wide range of BBB-expressed solute carriers (SLC's) were detected at the mRNA level. The presence and localization of SLC transporters GLUT1 and LAT1 was verified at the protein level. Functional studies revealed transport of the LAT1 substrate [3H]-L-Leucine and the LRP1 substrate angiopep-2. In conclusion, we have demonstrated that BIONi010-C-derived BCEC monolayers exhibited, BBB properties including barrier tightness and integrity, a high dynamic range, expression of some of the BBB receptor and transporter expression, as well as functional transport of LAT1 and LRP1 substrates. This suggests that BIONi010-C-derived BCEC monolayers may be useful for studying the roles of LAT-1 and LRP1 in brain drug delivery.

U2 - 10.1016/j.ejps.2020.105577

DO - 10.1016/j.ejps.2020.105577

M3 - Journal article

C2 - 33011235

VL - 156

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

M1 - 105577

ER -

ID: 249774103