Alcohol diminishes barrier integrity in human stem cell-derived brain microvascular endothelial cells: Role of reactive oxygen species.

The World Health Organization has linked alcohol consumption to over 200 diseases including neurodegenerative diseases. A dysfunctional blood-brain barrier (BBB) has been found to be influential in a number of brain disorders. The BBB is critical in maintaining homeostasis between the brain vasculature and parenchyma and a loss in barrier integrity would enable otherwise impermeable immune cells, molecules, and inflammatory mediators to reach the brain parenchyma. A subset of studies demonstrated that alcohol could diminish BBB integrity, but it is unclear if this effect translates clinically. In this study, we utilize a human stem cell-derived BBB model with near in vivo properties to investigate the effects of alcohol on critical barrier properties. Barrier forming brain-like microvascular endothelial cells (BMECs) were derived from human induced pluripotent stem cells (iPSCs) and exposed to several alcohol concentrations. Alcohol decreased barrier integrity observed by a loss in trans-endothelial electrical resistance and an increase in sodium fluorescein permeability. Alcohol decreased expression and junctional localization of tight junction proteins, a critical component to barrier integrity. Additionally, alcohol did not affect efflux transporter activity or cell viability in BMECs. The detrimental effects of alcohol on BBB properties were due to in part elevated reactive oxygen species (ROS); as scavenging ROS improved barrier properties, including the restoration of tight junction expression and localization. These data suggest that excessive alcohol consumption could diminish the BBB and contribute to the development or exacerbation of brain disorders. CLINICAL TRIAL NUMBER AND REGISTRY URL: Not applicable.