Recent progress and new challenges in modeling of human pluripotent stem cell-derived blood-brain barrier

The blood-brain barrier (BBB) is a semipermeable unit that serves to vascularize the central nervous system (CNS) while tightly regulating the movement of molecules, ions, and cells between the blood and the brain. The BBB precisely controls brain homeostasis and protects the neural tissue from toxins and pathogens. The BBB is coordinated by a tight monolayer of brain microvascular endothelial cells, which is subsequently supported by mural cells, astrocytes, and surrounding neuronal cells that regulate the barrier function with a series of specialized properties. Dysfunction of barrier properties is an important pathological feature in the progression of various neurological diseases. In vitro BBB models recapitulating the physiological and diseased states are important tools to understand the pathological mechanism and to serve as a platform to screen potential drugs. Recent advances in this field have stemmed from the use of pluripotent stem cells (PSCs). Various cell types of the BBB such as brain microvascular endothelial cells (BMECs), pericytes, and astrocytes have been derived from PSCs and synergistically incorporated to model the complex BBB structure in vitro. In this review, we summarize the most recent protocols and techniques for the differentiation of major cell types of the BBB. We also discuss the progress of BBB modeling by using PSC-derived cells and perspectives on how to reproduce more natural BBBs in vitro.