Abstract
IntroductionThe neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.MethodWe used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.ResultsThis system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.ConclusionThis model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.
Highlights
The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models
We describe expansion of this platform to generate a model of the arterial NVU composed of primary human Endothelial cells (EC), smooth-muscle cells (SMC) and astrocytes cultured in the presence of human induced pluripotent stem cells-derived glutamatergic cortical neurons
We further showed that induced pluripotent stem cell (iPSC)-derived neurons cultured in this bioengineered arterial NVU were electrically excitable and could both secrete glutamate and had measurable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents, suggesting possible synapse formation
Summary
The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. The brain consumes ~ 20% of total body oxygen and glucose utilization despite representing only 2% of total body mass [1, 2] These high metabolic demands vary both temporally and spatially in the brain, and are met by the coordinated action of several cell types known collectively as the neurovascular unit (NVU) [3, 4]. There is tremendous interest in developing cell-based models that mimic the BBB and NVU. Such models would greatly facilitate gaining a better understanding of the interactions between neurons and the vasculature in both physiological and pathophysiological conditions. If made with human cells, they would provide an invaluable translational platform for the development of neurotherapeutics
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