Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation

Area of Science:

• Neuroscience
• Developmental Biology
• Stem Cell Biology

Background:

• Human brain organoids model embryonic brain development but face limitations like hypoxia and cell death in later stages.
• Insufficient surface diffusion in current organoids prevents recapitulating late developmental stages.

Purpose of the Study:

• To develop a novel organoid system that overcomes diffusion limitations for long-term culture.
• To model late-stage human neocortical development and investigate disease mechanisms.

Main Methods:

• Introduction of the sliced neocortical organoid (SNO) system to bypass diffusion limits.
• Long-term culture of SNOs to enable sustained neurogenesis and development.
• Utilizing patient-derived induced pluripotent stem cells (iPSCs) for disease modeling.

Main Results:

• Sustained neurogenesis and formation of an expanded cortical plate in SNOs.
• Establishment of distinct upper and deep cortical layers, resembling the third trimester human neocortex.
• Identification of WNT/β-catenin signaling's role in human cortical neuron subtype fate specification.
• Demonstration of disrupted WNT/β-catenin signaling in SNOs derived from iPSCs with a psychiatric disorder-associated mutation.

Conclusions:

• The SNO system enables unprecedented investigation of late-stage human cortical development.
• SNOs are valuable for studying human-specific developmental mechanisms and disease-relevant pathways.
• This model provides insights into the genetic basis of psychiatric disorders affecting cortical development.