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Open Access 01-12-2018 | Research

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

Published in: Fluids and Barriers of the CNS | Issue 1/2018

Abstract

Background

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene. 40% of X-ALD patients will convert to the deadly childhood cerebral form (ccALD) characterized by increased permeability of the brain endothelium that constitutes the blood–brain barrier (BBB). Mutation information and molecular markers investigated to date are not predictive of conversion. Prior reports have focused on toxic metabolic byproducts and reactive oxygen species as instigators of cerebral inflammation and subsequent immune cell invasion leading to BBB breakdown. This study focuses on the BBB itself and evaluates differences in brain endothelium integrity using cells from ccALD patients and wild-type (WT) controls.

Methods

The blood–brain barrier of ccALD patients and WT controls was modeled using directed differentiation of induced pluripotent stem cells (iPSCs) into induced brain microvascular endothelial cells (iBMECs). Immunocytochemistry and PCR confirmed characteristic expression of brain microvascular endothelial cell (BMEC) markers. Barrier properties of iBMECs were measured via trans-endothelial electrical resistance (TEER), sodium fluorescein permeability, and frayed junction analysis. Electron microscopy and RNA-seq were used to further characterize disease-specific differences. Oil-Red-O staining was used to quantify differences in lipid accumulation. To evaluate whether treatment with block copolymers of poly(ethylene oxide) and poly(propylene oxide) (PEO–PPO) could mitigate defective properties, ccALD-iBMECs were treated with PEO–PPO block copolymers and their barrier properties and lipid accumulation levels were quantified.

Results

iBMECs from patients with ccALD had significantly decreased TEER (2592 ± 110 Ω cm²) compared to WT controls (5001 ± 172 Ω cm²). They also accumulated lipid droplets to a greater extent than WT-iBMECs. Upon treatment with a PEO–PPO diblock copolymer during the differentiation process, an increase in TEER and a reduction in lipid accumulation were observed for the polymer treated ccALD-iBMECs compared to untreated controls.

Conclusions

The finding that BBB integrity is decreased in ccALD and can be rescued with block copolymers opens the door for the discovery of BBB-specific molecular markers that can indicate the onset of ccALD and has therapeutic implications for preventing the conversion to ccALD.

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Title: Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients
Publication date: 01-12-2018
Published in: Fluids and Barriers of the CNS / Issue 1/2018
Electronic ISSN: 2045-8118
DOI: https://doi.org/10.1186/s12987-018-0094-5

At a glance: The STEP trials

Springer Medicine

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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Other articles of this Issue 1/2018

Challenges in cerebrospinal fluid shunting in patients with glioblastoma

The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus

Zika virus crosses an in vitro human blood brain barrier model

Accurate, strong, and stable reporting of choroid plexus epithelial cells in transgenic mice using a human transthyretin BAC

Sex-specific differences in organic anion transporting polypeptide 1a4 (Oatp1a4) functional expression at the blood–brain barrier in Sprague–Dawley rats