Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a fundamental structure that protects the composition of the brain by determining which ions, metabolites, and nutrients are allowed to enter the brain from the blood or to leave it towards the circulation. The BBB is structurally composed of a layer of brain capillary endothelial cells (BCECs) bound to each other through tight junctions (TJs). However, its development as well as maintenance and properties are controlled by the other brain cells that contact the BCECs: pericytes, glial cells, and even neurons themselves. Astrocytes seem, in particular, to have a very important role in determining and controlling most properties of the BBB. Here, we will focus on these latter cells, since the comprehension of their roles in brain physiology has been continuously expanding, even including the ability to participate in neurotransmission and in complex functions such as learning and memory. Accordingly, pathological conditions that alter astrocytic functions can alter the BBB's integrity, thus compromising many brain activities. In this review, we will also refer to different kinds of in vitro BBB models used to study the BBB's properties, evidencing its modifications under pathological conditions.

The neurovasculature as a target in temporal lobe epilepsy.

The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target.

Challenges and opportunities in the use of transcriptomic characterization of human iPSC-derived BBB models.

The blood-brain barrier (BBB) is localized at the brain microvascular endothelial cells. These cells form a tight barrier, limiting the access of cells, pathogens, chemicals, and toxins to the brain due to tight junctions and efflux transporters. As the BBB plays a role in the assessment of neurotoxicity and brain uptake of drugs, human in vitro BBB models are highly needed. They allow to evaluate if compounds could reach the central nervous system across the BBB or can compromise its barrier function. Past decade, multiple induced pluripotent stem cell (iPSC)-derived BBB differentiation protocols emerged. These protocols can be divided in two groups, the one-step protocols, direct differentiation from iPSC to BBB cells, or the two-step protocols, differentiation for iPSC to endothelial (progenitor) cells and further induction of BBB characteristics. While the one-step differentiation protocols display good barrier properties, reports question their endothelial nature and maturation status. Therefore protocol characterization remains important. With transcriptomics becoming cheaper, this may support iPSC-derived model characterization. Because of the constraints in obtaining human brain tissue, good human reference data is scarce and would bear inter-individual variability. Additionally, comparison across studies might be challenging due to variations in sample preparation and analysis. Hopefully, increasing use of transcriptomics will allow in-depth characterization of the current iPSC-BBB models and guide researchers to generate more relevant human BBB models.