Self-organizing human dual neural organoids model regional disease defects and teratogenicity

Abstract

The human nervous system emerges during early embryogenesis through coordinated, self-organizing differentiation of peripheral and central lineages. A key event in this process is the emergence of neural crest from the dorsal neural tube, which gives rise to major peripheral nervous system (PNS) structures. However, current in vitro models face challenges in recapitulating this process, limiting mechanistic insights into human central-peripheral neurogenesis. Here, we report a method for generating human peripheral-central dual neural organoids (hPCOs), a self-organizing organoid system that recapitulates the co-development of peripheral sensory ganglia and dorsal spinal cord. Using hPCOs, we uncover an unexpected bidirectional role of Wnt signaling in orchestrating peripheral and central fate determination. Modeling with hPCOs reveals nociceptor defects in human congenital insensitivity to pain. Furthermore, integrating hPCOs with image analysis enables the visual assessment of teratogenic risks. Together, hPCOs provide a physiologically relevant platform for investigating human self-organized central nervous system (CNS)-PNS co-development, disease mechanisms, and drug discovery.