Guided and unguided neural organoids play complementary roles in studying neurodevelopment and neuroinflammation

Objective:  This study aimed to compare guided dorsal forebrain neural organoids with unguided neural organoids, focusing on differences in structural organization, cellular composition, and functional properties.

Methods:  Using the same human induced pluripotent stem cell line, we applied two established differentiation protocols in parallel to generate guided and unguided neural organoids.

Results:  Guided neural organoids exhibited reproducible cytoarchitecture, relatively homogeneous morphology, and robust network activity, making them particularly well-suited for modeling specific aspects of cortical neurodevelopment and neurodevelopmental disorders. In contrast, unguided neural organoids displayed greater heterogeneity in morphology and cellular composition, including prominent development of astrocytes, microglia, and choroid plexus-like structures that respond to inflammatory stimuli, positioning them as valuable models for studying neuroinflammation during brain development.

Conclusion:  These findings emphasize the importance of selecting neural organoids protocols based on specific research questions, and suggest that the guided and unguided approaches can complement each other to provide insights into neurodevelopmental and neuroinflammatory processes.

Keywords:
Induced pluripotent stem cells; Guided dorsal forebrain neural organoids; Unguided neural organoids; Malformations of cortical development; Neuroinflammatory diseases

■Guided cortical neural organoids show consistent cytoarchitecture and robust network activity.

■Unguided neural organoids are heterogeneous, with glia, microglia, and choroid plexus cells.

■Guided neural organoids suit cortical development and neurodevelopmental disease studies.

■Unguided neural organoids are ideal for modeling neuroinflammation and diverse cell interactions.

Neural organoids model human brain development using guided or unguided approaches. Josino et al. showed that guided cortical neural organoids have consistent cytoarchitecture and robust network activity, ideal for cortical development and disease studies, while unguided neural organoids are more diverse, with glia, choroid plexus-like structures, and inflammatory responses, suited for neuroinflammation research.