Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis

Area of Science:

• Neuroscience
• Biotechnology
• Vascular Biology

Background:

• Cerebral organoids (COs) are valuable 3D brain models but lack physiological accuracy due to absent vascularization.
• Current vascularization methods face challenges including cell requirement differences, limited network penetration, and lack of perfusion.

Purpose of the Study:

• To develop a novel method for vascularizing cerebral organoids.
• To create a more physiologically relevant 3D neurovascular model for research and drug testing.

Main Methods:

• An encapsulation technique was used, delivering human brain microvascular endothelial cells (HBMVECs) within degrading extracellular matrix (ECM)-based hydrogel droplets to developing COs.
• Hydrogel concentration and media composition were optimized to promote vascular network formation.
• Pathway inhibitors were employed to identify the origin of endothelial cells (ECs) within the organoid.

Main Results:

• An enhanced, brain-like vascular network formed and expanded within the COs.
• A subset of ECs originated from the CO itself, integrating into the network.
• The vascularized COs exhibited key blood-brain barrier (BBB) features, including astrocytic interactions, pericyte wrapping, and basal lamina formation.
• Vascularized COs showed improved media uptake and significantly reduced apoptosis compared to non-vascularized controls.

Conclusions:

• The developed encapsulation method successfully creates vascularized cerebral organoids.
• This 3D neurovascular model offers enhanced physiological relevance for studying brain development, diseases, and testing therapeutics.
• The model holds promise for advancing cerebrovascular research and pharmaceutical applications.