Breaking Barriers: Modeling the Blood–Brain Barrier in Parkinson's Disease Using a Human‐Brain‐Chip

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-synuclein (ɑSyn) in the substantia nigra (SN) region of the brain. The use of in vivo and in vitro models has contributed to the current understanding of PD; however, these models are limited in their translational applications to human PD pathology. In vivo models are costly, and animals have fewer similarities in their cellular response when compared to humans, especially in the mechanisms driving disease induction. In vitro models can lack fluid flow, cell–cell interactions, and spatial neurovascular architecture.1 The organs-on-a-chip technology, specifically, neural-systems-on-a-chip (NSCs), has emerged as a revolutionary approach of creating models that simulate the human cellular environment by using the human-induced pluripotent stem cells (hiPSCs).2 Until recently, most developed NSCs did not recreate a vascular-neuronal interface with hiPSC-derived SN cells, use abnormal fibril aggregation to model blood–brain-barrier (BBB) dysfunction, or use therapeutic drugs to restore BBB function. Pediaditakis et al2 filled these gaps by developing a more specialized NSC: substantia nigra brain-chip (SNc). This SNc provides a promising model for the mechanism of the ɑSyn inflammatory response in PD. Pediaditakis et al2 used their previous organs-on-a-chip protocol3 to develop an NSC three-dimensional circuit chip with vascular and brain channels consisting of hiPSCs. The SNc demonstrated closer similarities in the gene expression levels of PD-related genes as seen in healthy SN tissue and replicated the activation of glial cells along with BBB permeability dysfunction2; a novel feature of this SNc compared to previous models. Furthermore, they used human ɑSyn fibrils to simulate an inflammatory response (a disrupted BBB) similar to a healthy brain and later ameliorated the inflammation with the therapeutic agent trehalose within 72 hours.2 These authors developed a more reproducible NSC than previous models by using well-characterized and well-established cell sources. However, advancement in the use of stem cells is yet to reach the point of having isogenic (using cell types originating from the same human) models because of lack of reproducibility and variability between each human sample. Critical advancements in this field will be achieving an isogenic model that can be used for various diseases and in various lab environments. The authors' SNc may be a pivotal step to better characterize the response to PD therapies, identify and evaluate associated biomarkers of PD, and create a reproducible NSC. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.