Experimental Comparison of Primary and hiPS-Based In Vitro Blood-Brain Barrier Models for Pharmacological Research

In vitro model systems of the blood-brain barrier (BBB) play an essential role in pharmacological research, specifically during the development and preclinical evaluation of new drug candidates. Within the past decade, the trend in research and further development has moved away from models based on primary cells of animal origin towards differentiated models derived from human induced pluripotent stem cells (hiPSs). However, this logical progression towards human model systems from renewable cell sources opens up questions about the transferability of results generated in the primary cell models. In this study, we have evaluated both models with identical experimental parameters and achieved a directly comparable characterisation showing no significant differences in protein expression or permeability even though the achieved transendothelial electrical resistance (TEER) values showed significant differences. In the course of this investigation, we also determined a significant deviation of both model systems from the in vivo BBB circumstances, specifically concerning the presence or absence of serum proteins in the culture media. Thus, we have further evaluated both systems when confronted with an in vivo-like distribution of serum and found a notable improvement in the differential permeability of hydrophilic and lipophilic compounds in the hiPS-derived BBB model. We then transferred this model into a microfluidic setup while maintaining the differential serum distribution and evaluated the permeability coefficients, which showed good comparability with values in the literature. Therefore, we have developed a microfluidic hiPS-based BBB model with characteristics comparable to the established primary cell-based model.

Automated summary

Models of the blood-brain barrier derived from human induced pluripotent stem cells (hiPSs) have shown comparable characteristics to primary cell-based models. Although there were no significant differences in protein expression or permeability, both models deviated from in vivo BBB conditions, specifically regarding the presence or absence of serum proteins. By adjusting the serum distribution, the hiPS-derived BBB model demonstrated improved permeability for hydrophilic and lipophilic compounds. The model was further developed in a microfluidic setup and exhibited comparable permeability coefficients to literature values.