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J Cereb Blood Flow Metab. 2018 Jun 18:271678X18783372. doi: 10.1177/0271678X18783372. [Epub ahead of print]

Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier.

Author information

1
1 Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA.
2
2 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
3
3 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
4
4 Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
5
5 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
6
6 Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
7
7 Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA.

Abstract

Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis, and energy production. Loss of brain iron homeostasis is a significant factor in multiple neurological disorders. Understanding the mechanism by which the transport of iron across the blood-brain barrier (BBB) is regulated is crucial to address the impact of iron deficiency on brain development and excessive accumulation of iron in neurodegenerative diseases. Using induced pluripotent stem cell (iPSC)-derived brain endothelial cells (huECs) as a human BBB model, we demonstrate the ability of transferrin, hepcidin, and DMT1 to impact iron transport and release. Our model reveals a new function for H-ferritin to transport iron across the BBB by binding to the T-cell immunoglobulin and mucin receptor 1. We show that huECs secrete both transferrin and H-ferritin, which can serve as iron sources for the brain. Based on our data, brain iron status can exert control of iron transport across the endothelial cells that constitute the BBB. These data address a number of pertinent questions such as how brain iron uptake is regulated at the regional level, the source of iron delivery to the brain, and the clinical strategies for attempting to treat brain iron deficiency.

KEYWORDS:

Blood–brain barrier; H-ferritin; iron; transferrin; transferrin receptor

PMID:
29911470
DOI:
10.1177/0271678X18783372

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