Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood‒brain barrier.

Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood-brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium.

Blood-brain barrier regulation: Environmental cues controlling the onset of barrier properties.

The existence of a barrier between the central nervous system (CNS) and the systemic circulation has been described over one hundred years ago. Since the discovery that this barrier was instigated by the barrier properties of the brain endothelial cells, research has focused on the identification of pathways how the brain endothelial cells are instructed to form the highly specialized blood-brain barrier (BBB). Even though our current understanding of BBB development is far from complete, recent literature shows a rise in knowledge of CNS-specific cues that can drive BBB development.   In this commentary, we will provide a brief overview of brain selective factors that are critical in the development of barrier properties in the brain endothelium; in particular the role of retinoic acid will be discussed.