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Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells

The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge g...

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Autores principales: Nielsen, Simone S. E., Holst, Mikkel R., Langthaler, Kristine, Christensen, Sarah Christine, Bruun, Elisabeth Helena, Brodin, Birger, Nielsen, Morten S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830855/
https://www.ncbi.nlm.nih.gov/pubmed/36624498
http://dx.doi.org/10.1186/s12987-022-00404-1
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author Nielsen, Simone S. E.
Holst, Mikkel R.
Langthaler, Kristine
Christensen, Sarah Christine
Bruun, Elisabeth Helena
Brodin, Birger
Nielsen, Morten S.
author_facet Nielsen, Simone S. E.
Holst, Mikkel R.
Langthaler, Kristine
Christensen, Sarah Christine
Bruun, Elisabeth Helena
Brodin, Birger
Nielsen, Morten S.
author_sort Nielsen, Simone S. E.
collection PubMed
description The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-022-00404-1.
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spelling pubmed-98308552023-01-11 Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells Nielsen, Simone S. E. Holst, Mikkel R. Langthaler, Kristine Christensen, Sarah Christine Bruun, Elisabeth Helena Brodin, Birger Nielsen, Morten S. Fluids Barriers CNS Research The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-022-00404-1. BioMed Central 2023-01-09 /pmc/articles/PMC9830855/ /pubmed/36624498 http://dx.doi.org/10.1186/s12987-022-00404-1 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Nielsen, Simone S. E.
Holst, Mikkel R.
Langthaler, Kristine
Christensen, Sarah Christine
Bruun, Elisabeth Helena
Brodin, Birger
Nielsen, Morten S.
Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title_full Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title_fullStr Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title_full_unstemmed Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title_short Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
title_sort apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830855/
https://www.ncbi.nlm.nih.gov/pubmed/36624498
http://dx.doi.org/10.1186/s12987-022-00404-1
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