Closing the sex/gender gap in dementia: homing in on the vasculature (in vitro/iPSCs)

Abstract

AbstractInduced pluripotent stem cell (iPSC) models are increasingly being used to model the blood brain barrier (BBB) and to examine the contributions of genetic risk factors to neurovascular disease. While clinical and rodent studies clearly demonstrate the importance of sex in vascular‐related neurodegeneration, only a handful of published studies have thus far begun to employ iPSC modeling to examine the biology that underlies these sex‐related differences. Early reports suggested that female iPSC‐derived brain microvascular endothelial cells (BMECs) exhibit increased transendothelial electrical resistance (TEER) and thus decreased permeability than male BMEC counterparts. Conversely, male pluripotent cells were found to differentiate more readily into BMECs. However, these initial studies were often underpowered and failed to account for the considerable variability inherent between iPSC lines. More recently, consortiums have begun to generate and examine BMECs and glia from a large number of subjects with various neurodegenerative diseases. While much of this work is currently unpublished, these large‐scale datasets further support the concept that sex alters the transcriptome and function of BMECs and vascular‐associated glia. The development and use of ‘isogenic’ male and female iPSC lines derived from Klinefelter syndrome subjects is providing another powerful new approach to study sex‐dependent effects on cellular function. Both the complexity and utility of in vitro iPSC‐modeling of brain vasculature continues to improve and now includes both bioengineered vascular networks and vascularized organoids. In addition, recent progress with xenotransplantation models is providing further avenues to study the interactions between human glial, blood brain barrier function, and cerebral amyloid angiopathy. Nevertheless, there remains a pressing need to further examine and understand both the intrinsic and extrinsic effects of sex on BBB function and vascular‐related neurodegenerative disease, a topic that will be extensively discussed during this AAIC perspectives panel.