Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

Abstract

Huntington’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 suggest 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 alters the trajectory of iBMEC differentiation, producing cells with ~ 2-fold lower purity of adherent endothelial cells. CAG expansion is associated with lower transendothelial electrical resistance, lower tight junction protein expression, and unique gene expression profiles, but no significant changes in paracellular permeability. In addition, CAG expansion results in unique 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 may alter BBB phenotype during HD.