Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease
-
Published:2022-06-30
Issue:1
Volume:19
Page:
-
ISSN:2045-8118
-
Container-title:Fluids and Barriers of the CNS
-
language:en
-
Short-container-title:Fluids Barriers CNS
Author:
Linville Raleigh M.,Nerenberg Renée F.,Grifno Gabrielle,Arevalo Diego,Guo Zhaobin,Searson Peter C.
Abstract
AbstractHuntington’s disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood–brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.
Funder
National Institute of Neurological Disorders and Stroke Defense Threat Reduction Agency National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Developmental Neuroscience,Neurology,General Medicine
Reference55 articles.
1. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ. Huntington disease. Nat Rev Dis Primers. 2015;1:15005. 2. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev. 2010;90(3):905–81. 3. Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagace M, Kuan WL, Saint-Pierre M, Dury RJ, Alata W, St-Amour I, Mason SL, Calon F, Lacroix S, Gowland PA, Francis ST, Barker RA, Cicchetti F. Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology. Ann Neurol. 2015;78(2):160–77. 4. Di Pardo A, Amico E, Scalabri F, Pepe G, Castaldo S, Elifani F, Capocci L, De Sanctis C, Comerci L, Pompeo F, D’Esposito M, Filosa S, Crispi S, Maglione V. Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease. Sci Rep. 2017;7:41316. 5. Lim RG, Quan C, Reyes-Ortiz AM, Lutz SE, Kedaigle AJ, Gipson TA, Wu J, Vatine GD, Stocksdale J, Casale MS, Svendsen CN, Fraenkel E, Housman DE, Agalliu D, Thompson LM. Huntington’s disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated angiogenic and blood-brain barrier deficits. Cell Rep. 2017;19(7):1365–77.
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|