Neural Sheets: Engineering Next-Generation Human Brain Models via Apicobasal Polarity-Guided Directional Neurogenesis

Form dictates function – a fundamental biological principle underlying the complexity of multicellular life. Nowhere is this more evident than in the human brain, whose tightly orchestrated architecture enables cognition, perception, and consciousness. However, many features of human brain development – including cortical layering, grey/white matter, and gyrification – are not captured by current in vitro 2D/3D models, drastically limiting our ability to study human-specific neurodevelopment, function and disease. In Neural Sheets, I aim to radically advance our understanding of human brain development and overcome critical limitations of current in vitro models. This work will unfold across four integrated aims: 1. Mechanism: I will investigate how a group of apical-inducing lipids repositions (neuro)epithelial polarity. 2. Platform: I will engineer a scalable neuroepithelial platform (“Neural Sheets”) that will sustain organized progenitor sheets and enable directional, extended neurogenesis. 3. Support Modules: I will develop a tissue grid perfusion stamper and scalable perfusion system for long-term proliferation and maturation to enable cortical layering and grey/white matter organization. 4. Cortical phenotyping: I will perform connectivity mapping, physiology and transcriptomics and benchmark against human developmental cortex references. Neural Sheets will make polarity and shape programmable, enabling a ground-breaking new class of reproducible human brain models for mechanistic studies.