In-vitro iPSC based neuro-vascular unit for drug screening

The Blood-Brain Barrier (BBB) constitutes a neuro-vascular unit (NVU), comprised of astrocytes, pericytes, neurons and brain microvascular endothelial cells (BMECs) – all of them interacting to form a barrier between the circulatory system and the Central-Nervous System (CNS). One of the main challenges in drug development today is on one hand, enhancing CNS-targeted drug delivery to the CNS, and on the other, preventing unwanted substances from reaching there. Marked differences in BBB physiology and transport mechanisms across species limit the relevance of animal models for predicting CNS penetrability.

Induced pluripotent stem-cells (iPSCs) provide an attractive source of BMECs. Here, we are developing an in vitro dual-compartment NVU system based on Transwell and microelectrode array (MEA) systems. The top, endothelial compartment is seeded with iPSC-derived BMECs that form a continuous monolayer, expressing tight-junction proteins over a porous membrane, which achieve physiologically relevant transepithelial electrical resistance (TEER). The bottom, neural compartment contains primary brain cells isolated from rat striatum, seeded on a Microelectrode Array (MEA), allowing real time electrophysiological measurements. Our preliminary results show that iBMECs growing over primary striatal rat cells displayed increased TEER compared with iBMECs growing over fibroblasts or as a monoculture. These results demonstrate the potential of our approach to simulate physiological conditions, and together with the ability of using multi-well plates containing multiple systems to develop a high throughput platform for drug screening and development.