Bidirectional apical-basal traffic of the cation-independent mannose-6-phosphate receptor in brain endothelial cells.
Brain capillary endothelium mediates the exchange of nutrients between blood and brain parenchyma. This barrier function of the brain capillaries also limits passage of pharmaceuticals from blood to brain, which hinders treatment of several neurological disorders. Receptor-mediated transport has been suggested as a potential pharmaceutical delivery route across the brain endothelium, e.g. reports have shown that the transferrin receptor (TfR) facilitates transcytosis of TfR antibodies, but it is not known whether this recycling receptor itself traffics from apical to basal membrane in the process. Here, we elucidate the endosomal trafficking of the retrograde transported cation-independent mannose-6-phosphate receptor (MPR300) in primary cultures of brain endothelial cells (BECs) of porcine and bovine origin. Receptor expression and localisation of MPR300 in the endo-lysosomal system and trafficking of internalised receptor are analysed. We also demonstrate that MPR300 can undergo bidirectional apical-basal trafficking in primary BECs in co-culture with astrocytes. This is, to our knowledge, the first detailed study of retrograde transported receptor trafficking in BECs, and the study demonstrates that MPR300 can be transported from the luminal to abluminal membrane and reverse. Such trafficking of MPR300 suggests that retrograde transported receptors in general may provide a mechanism for transport of pharmaceuticals into the brain.
1 Department of Biomedicine, Aarhus University, Aarhus, Denmark.|2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.
Piotr
P
Siupka
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|3 Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
Maria Ns
MN
Hersom
1 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Karin
K
Lykke-Hartmann
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|4 Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.|5 Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Denmark.
Kasper B
KB
Johnsen
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|4 Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Louiza B
LB
Thomsen
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|5 Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Denmark.
Thomas L
TL
Andresen
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|4 Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Torben
T
Moos
6 Institute of Pharmaceutical Science, King's College London, London, UK.
N Joan
NJ
Abbott
2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.|3 Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
Birger
B
Brodin
1 Department of Biomedicine, Aarhus University, Aarhus, Denmark.|2 Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Aarhus, Denmark.
Morten S
MS
Nielsen
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D013552:Swine
D004364:Pharmaceutical Preparations; D017527:Receptor, IGF Type 2
Mannose-6-phosphate receptors; blood–brain barrier; brain endothelial cells; trafficking; transcytosis