Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease

The high metabolic demands of the brain require an efficient vascular system to be coupled with neural activity to supply adequate nutrients and oxygen. This supply is coordinated by the action of neurons, glial and vascular cells, known collectively as the neurovascular unit, which temporally and spatially regulate local cerebral blood flow through a process known as neurovascular coupling. In many neurodegenerative diseases, changes in functions of the neurovascular unit not only impair neurovascular coupling but also permeability of the blood-brain barrier, cerebral blood flow and clearance of waste from the brain. In order to study disease mechanisms, we need improved physiologicallyrelevant human models of the neurovascular unit. Advances towards modeling the cellular complexity of the neurovascular unit in vitro have been made using stem-cell derived organoids and more recently, vascularized organoids, enabling intricate studies of non-cell autonomous processes. Engineering and design innovations in microfluidic devices and tissue engineering are progressing our ability to interrogate the cerebrovasculature. These advanced models are being used to gain a better understanding of neurodegenerative disease processes and potential therapeutics. Continued innovation is required to build more physiologically-relevant models of the neurovascular unit encompassing both the cellular complexity and designed features to interrogate neurovascular unit functionality.