Blood‐brain barrier development: Systems modeling and predictive toxicology

Abstract

The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high-content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function. Computational models are needed that bring together kinetic and dynamic aspects of NVU function across gestation and under various physiological and toxicological scenarios. This integration will inform adverse outcome pathways to reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect neurodevelopmental health.

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

“…Interactions between these NVU cell types is important for a variety of physiological processes such as angiogenesis, vessel maintenance and permeability, metabolic support, and regulation of blood flow (Brown et al 2019;McConnell et al 2017). The development of the NVU begins around embryonic day (E) 9.5 in mice, when specialized endothelial cells branch from vessels of the perineural vascular plexus to form capillaries that invade nearby neural tissue (Saili et al 2017). Pericytes associate with endothelial cells as nascent vessels generate at E9.5 (Armulik et al 2010;Bauer et al 1993;Yamanishi et al 2012;Daneman et al 2010) and these interactions are critical to form the BBB (Zlokovic 2008;Daneman et al 2010).…”

Invisible Designers: Brain Evolution Through the Lens of Parasite Manipulation

“…The Blood-Brain Barrier as a Chemical Defense Another key function of the BBB is to regulate the flux of neurotransmitters/neuromodulators, hormones, and other molecules from the blood to the brain and vice versa. The brief summary that follows is based on studies of mammals such as rats, dogs, and humans, even though several BBB mechanisms are surprisingly conserved in both vertebrates and invertebrates (see DeSalvo et al 2014;Hindle and Bainton 2014;Hindle et al 2017;Saili et al 2017). For some molecules such as serotonin and steroid hormones, the flux is bidirectional; other molecules only flow from the blood to the brain (influx) as, for example, insulin and thyroid hormone.…”

“…The molecules that are only transported out of the brain (efflux) include GABA, glutamate, norepinephrine, dopamine, and the dopamine metabolite homovanillic acid (HVA). There are also active transporters that expel a variety of toxins and other foreign substances (xenobiotics), as well as metabolizing enzymes that inactivate them (Ohtsuki 2004;Banks 2012;Zhao et al 2015;Saili et al 2017). By clearing neuroactive molecules such as dopamine and GABA, the BBB probably contributes to regulate neurotransmission (Ohtsuki 2004).…”

Neurovascular Organotypic Culture Models Using Induced Pluripotent Stem Cells to Assess Adverse Chemical Exposure Outcomes

“…2,3 OCMs are being constructed from increasingly advanced materials and human stem cell sources, including embryonic stem cells and induced pluripotent stem cells (iPSCs). 4 A critical tissue of interest for modeling chemical toxicity is the neurovasculature of the central nervous system (CNS), which supplies blood to the brain, spinal cord, and the eye.…”

“…Endothelial cells (ECs) of the neurovascular interact with supporting cell types, including astrocytes (ACs), pericytes (PCs), and neurons to form the neurovascular unit (NVU), 4 which maintains stable blood flow to and from the CNS. Hypoxia, ischemia, and cerebral hypoperfusion resulting from NVU failure can cause the onset of neurodevelopmental or neurodegenerative diseases, including Alzheimer's disease, [5][6][7][8] Parkinson's disease, 9,10 autism spectrum disorders, 11,12 and diabetic retinopathy.…”