In vitro models
One longstanding goal of BBB research has been the development of cell-based in vitro experimental models that accurately mimic the BBB characteristics observed in vivo. Such models would be amenable to drug permeability screening and a priori prediction of brain uptake.
We recently focused our efforts on utilizing human pluripotent stem cells (hPSCs) for BBB modeling purposes. As such, we have developed novel methods for differentiating hPSCs, including both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into human endothelial cells with specific properties of the BBB. These hPSC-derived BMECs express transcript and protein markers of the BBB, exhibit extremely high TEER, and possess active efflux transporters, which allows them to discriminate between small molecule drugs with varying efflux transporter recognition properties in an in vitro permeability screen.
We have also developed methods to differentiate hPSCs to other cell types of the neurovascular unit (NVU) including astrocytes, neurons, and pericytes, which interact with BBB-forming endothelial cells and dynamically regulate BBB properties. We have employed these models to study a genetic disorder of the BBB and BBB-pathogen interactions.
Representative Publications
- Gastfriend BD et al. (2024). Notch3 directs differentiation of brain mural cells from human pluripotent stem cell–derived neural crest. Sci Adv doi: 10.1126/sciadv.adi1737.
- Gastfriend BD et al. (2021). Wnt signaling mediates acquisition of blood–brain barrier properties in naïve endothelium derived from human pluripotent stem cells. ELife doi: 10.7554/eLife.70992.
- Nishihara H et al. (2020). Advancing human induced pluripotent stem cell-derived blood-brain barrier models for studying immune cell interactions. FASEB J doi: 10.1096/fj.202001507RR.
- Stebbins MJ et al. (2019). Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties. Sci Adv 5:eaau7375.
- Kim BJ et al. (2017). Modeling Group B Streptococcus and blood-brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells. mSphere 2:e00398-17.
- Vatine GD et al.(2017). Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell 20:831-43.
- Canfield SG et al. (2017). An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem 140:874-88.