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Cell Rep. 2017 May 16;19(7):1365-1377. doi: 10.1016/j.celrep.2017.04.021.

Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.

Author information

1
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; UCI MIND, University of California, Irvine, Irvine, CA 92697, USA.
2
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Sciences, California State University, Long Beach, 1250 Bellflower Boulevard, Long Beach, CA 90840, USA.
3
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
4
Departments of Neurology, Pathology, and Cell Biology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
5
Computational and Systems Biology Graduate Program, MIT, Cambridge, MA 02139, USA.
6
Center for Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
7
Department of Biomedical Sciences, The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
8
UCI MIND, University of California, Irvine, Irvine, CA 92697, USA.
9
Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
10
Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
11
Departments of Neurology, Pathology, and Cell Biology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA; Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: da191@cumc.columbia.edu.
12
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; UCI MIND, University of California, Irvine, Irvine, CA 92697, USA; Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA; Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: lmthomps@uci.edu.

Abstract

Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.

KEYWORDS:

BMEC; Huntington’s disease; RNA sequencing; WNT signaling; angiogenesis; blood-brain barrier; brain microvascular endothelial cell; epigenetics; induced pluripotent stem cell; neurodegeneration; transcriptome

PMID:
28514657
PMCID:
PMC5646270
DOI:
10.1016/j.celrep.2017.04.021
[Indexed for MEDLINE]
Free PMC Article

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