Engineering a Human Blood Brain Barrier Model from Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery
Abstract: The blood-brain barrier (BBB) is critical in maintaining brain homeostasis and disrupted BBB is associated with many neurological diseases. The BBB consists of brain microvascular endothelial cells (BMECs) that line the brain vasculature and astrocytes, neurons and pericytes which regulate BMEC function as part of the neurovascular unit (NVU). We have developed methods to differentiate human induced pluripotent stem cells (iPSCs) to each of the neurovascular unit cell types and combined these to construct an in vitro model of the human BBB that displays physiologic barrier function and BBB-specific active transporter expression. We can generate BMECs that progress through mesoderm and endothelial progenitors by activating Wnt and retinoic acid signaling at appropriate differentiation stages while brain specific pericytes arise from iPSC-derived neural crest progenitors. Using patient-specific iPSCs, we demonstrated that MCT8 thyroid hormone transporter is necessary for thyroid hormone transport across the BBB, suggesting that MCT8 deficiency affects neuronal development by slowing thyroid hormone transport into the brain. We anticipate this isogenic model of the BBB will have applications in furthering our understanding of intercellular interactions in the NVU in both healthy and diseased humans.