Development of Human in vitro Brain-blood Barrier Model from Induced Pluripotent Stem Cell-derived Endothelial Cells to Predict the in vivo Permeability of Drugs

Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System

“…To our knowledge this is the first study where an in vitro BBB model, established from iPSCs, has been characterized for the transport of as many as 23 molecules, with confirmation in a different clone indicating the reproducibility of the differentiation method. Li et al [21] showed a good correlation between values obtained in a human iPSC-derived model with those obtained using an in situ brain perfusion method in rats for a panel of nine compounds, segregated into PGP/BCRP substrates and non substrates, proposing the assay as second-line screening for CNS drug candidates. We previously demonstrated a good correlation between permeability in the porcine model and in vivo brain partition [2], and here we show that permeability data derived from the human and porcine assays are very similar (the full test set of 23 compounds correlated with a coefficient of determination R 2 of 0.8).…”

“…The results from Lippmann's group demonstrated the importance of co-culture with astrocytes in TEER increase [6]. Although some authors reported differentiation in the absence of supporting cells [14,[18][19][20], the group of Zhang [21] demonstrated how co-culture with astroglia ameliorates the barrier phenotype, increasing TEER and reducing LY permeability. For our transport studies, and similarly to Mabondzo's group [22] who clinically validated the system, we used only astrocytes as it has been reported that neither TEER nor permeability characteristics gained benefit from the presence of pericytes [23].…”

Recent advances in human iPSC-derived models of the blood–brain barrier

“…These models more accurately predict human BBB permeability compared to non-human BBB models [69] and hold great promise in providing a high-throughput platform for predicting human CNS drug permeabilities and circumventing the need for animal-based testing [70]. Early iPSC-derived BBB models highlighted the ability of iBMECs to correlate well with in vivo drug permeability using transwell systems [12,71] and subsequent studies have expanded permeability testing to microfluidic platforms under fluid flow that more closely mimic in vivo conditions [19,31,64]. Importantly, iBMECs express many of the necessary efflux pumps and transporters [18,31,39] and have successfully been used to investigate general drug transport as well as specific transporter-drug interactions such as LAT1 with gabapentin [72].…”

Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

“…Despite changes in the microenvironment and BBB permeability, this BBB model lacks astrocytes and pericytes which play an important role in the function of the BBB [91]. To overcome this issue, some models have incorporated rat astrocytes [121,122] and hiPSC-derived pericytes [123] with endothelial cells, astrocytes, and neurons to model the BBB. These BBB models show in vivo BBB characteristics with high transendothelial electrical resistance and expression of tight junction proteins [121][122][123][124][125][126].…”

“…To overcome this issue, some models have incorporated rat astrocytes [ 121 , 122 ] and hiPSC-derived pericytes [ 123 ] with endothelial cells, astrocytes, and neurons to model the BBB. These BBB models show in vivo BBB characteristics with high transendothelial electrical resistance and expression of tight junction proteins [ 121 – 126 ]. Despite these advances, the BBB platform and differentiation protocols still require optimization to develop functional vasculature in COs.…”