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

Ryan G Lim; Chris Quan; Andrea M Reyes-Ortiz; Sarah E Lutz; Amanda J Kedaigle; Theresa A Gipson; Jie Wu; Gad D Vatine; Jennifer Stocksdale; Malcolm S Casale; Clive N Svendsen; Ernest Fraenkel; David E Housman; Dritan Agalliu; Leslie M Thompson

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Blood-Brain Barrier / pathology*
Endothelial Cells / pathology*
Gene Regulatory Networks
Humans
Huntington Disease / genetics
Huntington Disease / pathology*
Induced Pluripotent Stem Cells / metabolism
Induced Pluripotent Stem Cells / pathology*
Microvessels / pathology*
Neovascularization, Physiologic*
Transcriptome / genetics
Transcytosis
Wnt Signaling Pathway*
beta Catenin / metabolism

Substances

beta Catenin

Abstract

Publication types

MeSH terms

Substances

Grants and funding