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.

Keywords: 3D models; blood-brain barrier; human; in vitro model; transwell.

Figure 1

Physiological structure of the BBB and pathological alteration. (A) Schematic illustration of cellular constituents of BBB: the anatomical seat of the BBB is endothelial cells, associated and supported by pericytes and astrocytic end-feet forming the cellular barrier. Endothelial cells are connected to each other by tight junction proteins which ensure the impermeability of the barrier and form a physical barrier. (B) In pathological conditions, the BBB will be affected, and there will be a decrease in blood flow, detachment of pericytes and astrocytes as well as loss of tight junction proteins. All this giving the possibility for toxic molecules to infiltrate the brain parenchyma.

Figure 2

Chronologic event in human BBB invitro models. Overtime, BBB models have evolved and became more complex to best reproduce physiological conditions. But each of these models have themselves evolved, in particular through the evolution of cell types.

Figure 3

Schematic illustration of the impact of inflammatory processes on BBB integrity.

Figure 4

Schematic illustration of neural dysregulation on in vitro human BBB models.

Figure 5

Schematic illustration of brain invasion on in vitro human BBB models.

Figure 6

Schematic illustration of cerebrovascular dysregulation on in vitro human BBB models.