3D Human BBB Organoid Model Accurately Recapitulates Neuroinflammation and Ischemia-Reperfusion Injury

Disruption of the blood-brain barrier (BBB) and subsequent immune cell infiltration are hallmarks of numerous central nervous system (CNS) pathologies, including neurodegenerative diseases and stroke. Current therapeutic strategies often struggle to effectively modulate this immune cell transmigration due to the BBB's protective nature and the complexity of neuroimmune interactions. Existing in vitro models, such as traditional 2D cultures or simpler organoids, frequently lack the cellular complexity and physiological relevance needed to fully capture these intricate interactions, hindering the development of targeted therapies that can control immune cell entry into the brain.

Researchers developed a 3D human BBB spheroidal model consisting of six major brain cell types: brain microvascular endothelial cells (HBMVECs) and pericytes forming the surface, surrounding a core of astrocytes, microglia, oligodendrocytes, and neural progenitor cells. This model was used to test CD4+ T-cell transmigration under normal conditions and pathological states induced by proinflammatory cytokines (e.g., TNF-α, IL-1β) or hypoxia-reperfusion injury (IRI). The study assessed changes in cell adhesion molecule expression on HBMVECs and measured barrier permeability. As a validation step, they also tested the effect of anti-cell adhesion molecule antibodies on immune cell transmigration.

The 3D human BBB model successfully recapitulated key features of the barrier under both normal and pathological conditions. Exposure to proinflammatory cytokines and hypoxia-reperfusion significantly disrupted the barrier, leading to increased permeability and a decrease in the expression of tight junctions. Furthermore, these pathological conditions markedly increased the expression of cell adhesion molecules on HBMVECs, which in turn promoted a substantial increase in immune cell transmigration across the barrier. This enhanced transmigration was a critical finding, demonstrating the model's ability to mimic in vivo immune responses. Importantly, the researchers observed that:

Immune cell transmigration could be effectively reduced with anti-cell adhesion molecule antibodies, further validating the model's utility for studying neuroimmune interactions and identifying potential therapeutic targets. This reduction highlights the critical role of adhesion molecules in facilitating immune cell entry into the brain during inflammatory and ischemic events.