Study of BBB Dysregulation in Neuropathogenicity Using Integrative Human Model of Blood–Brain Barrier

Abstract

The blood–brain barrier (BBB) is a cellular and physical barrier with a crucial role in homeostasis of the brain extracellular environment. It controls the imports of nutrients to the brain and exports toxins and pathogens. Dysregulation of the blood–brain barrier increases permeability and contributes to pathologies, including Alzheimer's disease, epilepsy, and ischemia. It remains unclear how a dysregulated BBB contributes to these different syndromes. Initial studies on the role of the BBB in neurological disorders and also techniques to permit the entry of therapeutic molecules were made in animals. This review examines progress in the use of human models of the BBB, more relevant to human neurological disorders. In recent years, the functionality and complexity of in vitro BBB models have increased. Initial efforts consisted of static transwell cultures of brain endothelial cells. Human cell models based on microfluidics or organoids derived from human-derived induced pluripotent stem cells have become more realistic and perform better. We consider the architecture of different model generations as well as the cell types used in their fabrication. Finally, we discuss optimal models to study neurodegenerative diseases, brain glioma, epilepsies, transmigration of peripheral immune cells, and brain entry of neurotrophic viruses and metastatic cancer cells.

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems

“…The blood–brain barrier (BBB) is a selective and permeable physical barrier with the role of protecting the central nervous system (CNS) environment. BBB restricts the access of a wide range of compounds into the CNS, including toxins, pathogens, antibodies, and immune cells, and simultaneously prevents the entrance of many therapeutic drugs [ 50 , 51 ].…”

“…The blood-brain barrier-penetrating potential, analyzed by computational models, indicates that crotalphine is not predicted to easily penetrate the blood–brain barrier, with a probability of only 0.36 and 0.12 ( Supplementary Methods and Results , Analysing tool for synthetic crotalphine physiochemical properties prediction and blood-brain barrier penetrating potential). However, it is known that several disorders and pathological conditions may dysregulate the BBB integrity and increase the permeability, such as stroke, brain tumors, meningoencephalitis, multiple sclerosis, and neuroinflammation [ 50 , 52 , 53 ], which allows the transmigration of activated cells and the entrance of several compounds into the CNS [ 54 ]. The manipulation of molecular transport through BBB for the flow of solutes into the brain has been widely described [ 53 , 55 , 56 ].…”

A human-derived neurovascular unit in vitro model to study the effects of cellular cross-talk and soluble factors on barrier integrity

“…To further support and optimize our findings on BBB permeability as well as correlate them to our TEER results more accurately, future work will explore the use of functional assays for P-glycoprotein (p-GP). Specifically, rhodamine 123 dye would represent a complementary approach to perform transport studies on the p-GP activity and BBB efflux ratio in our model setups, similarly to previous studies (Tai et al, 2009;Simöes Da Gama and Morin-Brureau, 2022). One way of improving the model is by integrating more types of cells found in the NVU, such as pericytes and microglia, as well as refining cell culture conditions to extend the timeline for more endpoints to study.…”

Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies

“…As many diseases could benefit from efficient delivery of AAV vectors to the brain or the lung, the identification of AAV serotypes/variants that can efficiently cross the BBB or PEB would have a substantial clinical impact. Human brain organoids that accurately model the functionality of the BBB have already been developed and used extensively to study the ability of therapeutics to access the central nervous system ( 89 , 151 – 155 ), to better understand alterations to the BBB that occur in various disease settings and during infection and the neuroinflammation that ensues due to BBB disruption ( 89 , 153 , 156 – 162 ), to study tumor metastasis ( 163 – 168 ), to examine receptor-mediated antibody transcytosis ( 169 – 171 ), and to develop and test novel nanoparticles for their ability to transit the BBB ( 172 , 173 ). Similarly, lung organoids have also been used to study epithelial barrier function under normal homeostasis and in response to infection, exposure to nanomaterials, environmental toxicants, and small particulates, as well as for screening of new pharmaceuticals ( 174 – 185 ).…”