Transcriptional Responses of in vitro Blood-Brain Barrier Models to Shear Stress

Endothelial cells throughout the body sense blood flow, eliciting transcriptional and phenotypic responses. Brain endothelium, known as the blood-brain barrier (BBB), possesses unique barrier and transport properties which are in part regulated by blood flow. We utilized next generation sequencing to analyze the transcriptome of primary cultured rat brain microvascular endothelial cells (BMECs) as well as three human induced pluripotent stem cell-derived models. We compared the transcriptional responses of these cells to either low (~0.5 dyne/cm2) or high (12 dyne/cm2) shear stresses, and subsequent analysis identified genes and pathways that were influenced by shear including key BBB-associated genes (SLC2A1, LSR, PLVAP) and canonical endothelial shear stress response transcription factors (KLF2, KLF4). In addition, our analysis suggests that shear alone is insufficient to rescue de-differentiation caused by in vitro primary BMEC culture. Overall, these datasets and analyses provide new insights into the role of shear on BBB models that will aid in model selection and guide further model development. Overall design: Stem cell derived and rat brain vasculature endothelial cells were exposed to shear stress at either 12 dyne/cm2 or 0.1 dyne/cm2 for 72 hours and mRNA was collected and sequenced