HUMAN SPINAL CORD ORGANOIDS REVEAL CELL INTERCALATION AS A CONSERVED MECHANISM FOR SECONDARY NEURULATION

Human pluripotent stem cells (hPSCs) have enabled major advances in neural organoid research, yet reconstructing spinal cord development in vitro remains challenging, as it requires mimicking the early environment of body axis elongation. Here, by exposing hPSCs to defined extrinsic signals, we directed their self-organizing capacity to generate organoids that recapitulate the transcriptional profile, cellular composition, and tissue architecture of the early human posterior spinal cord. Furthermore, we refined our culture system to more closely model the in vivo morphogenetic events of secondary neurulation. Using this approach, we identified cell intercalation--regulated by Yes-associated protein (YAP) activity--as a key morphogenetic mechanism driving de novo lumen formation and resolution. These biomimetic models provide a powerful platform to investigate the molecular and mechanical processes underlying human spinal cord development and offer new opportunities to elucidate the origins of neural tube defects, among the most common congenital defects.