Abstract
The blood–brain barrier (BBB) is a selective endothelial interface that controls trafficking between the bloodstream and brain interstitial space. During development, the BBB arises as a result of complex multicellular interactions between immature endothelial cells and neural progenitors, neurons, radial glia, and pericytes. As the brain develops, astrocytes and pericytes further contribute to BBB induction and maintenance of the BBB phenotype. Because BBB development, maintenance, and disease states are difficult and time-consuming to study in vivo, researchers often utilize in vitro models for simplified analyses and higher throughput. The in vitro format also provides a platform for screening brain-penetrating therapeutics. However, BBB models derived from adult tissue, especially human sources, have been hampered by limited cell availability and model fidelity. Furthermore, BBB endothelium is very difficult if not impossible to isolate from embryonic animal or human brain, restricting capabilities to model BBB development in vitro. In an effort to address some of these shortcomings, advances in stem cell research have recently been leveraged for improving our understanding of BBB development and function. Stem cells, which are defined by their capacity to expand by self-renewal, can be coaxed to form various somatic cell types and could in principle be very attractive for BBB modeling applications. In this review, we will describe how neural progenitor cells (NPCs), the in vitro precursors to neurons, astrocytes, and oligodendrocytes, can be used to study BBB induction. Next, we will detail how these same NPCs can be differentiated to more mature populations of neurons and astrocytes and profile their use in co-culture modeling of the adult BBB. Finally, we will describe our recent efforts in differentiating human pluripotent stem cells (hPSCs) to endothelial cells with robust BBB characteristics and detail how these cells could ultimately be used to study BBB development and maintenance, to model neurological disease, and to screen neuropharmaceuticals.
Highlights
The blood–brain barrier (BBB) is a selective endothelial interface that controls trafficking between the bloodstream and brain interstitial space
While the nature of the molecular signals imparted on the brain endothelial cells by the neighboring cells of the developing neurovascular unit remains unclear, recent studies have highlighted the importance of Wnt signaling, GPR124 and sonic hedgehog (Shh) [6,12,13,14,15,16,17,18]
If instead Neural progenitor cell (NPC) were differentiated for 24 hours in the absence of Brain microvascular endothelial cell (BMEC) prior to co-culture, the mixture contained more βIII tubulin+ neurons and fewer nestin-expressing precursors, but the co-cultures were unable to substantially induce elevated BMEC transendothelial electrical resistance (TEER). These results indicated that NPCs in their early stages of differentiation, likely in the nestin-expressing state, have the potential to induce Blood–brain barrier (BBB) properties in BMECs, and do so in a manner distinct in timing and duration from postnatal astrocytes
Summary
Stem cells have proven useful over the last decade for modeling various developmental and disease processes in humans. Advances in the genetic manipulation of hPSCs using tools such as bacterial artificial chromosomes [137], zinc finger nucleases [138], and TAL effector nucleases [139] could allow genetic manipulation akin to transgenic animal models to explore open-ended hypotheses regarding cell-specific and genetic contributions to disease states. While these strategies will likely always require an in vivo complement to verify experimental outcomes, they could substantially shorten exploratory endeavors and translate outcomes observed in animal studies to human cells. All authors have read and approved the final version of the manuscript
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