Transplantation of engineered spinal cord organoids restores functions after spinal cord injury

Abstract Generating functional maturation neural organoids to model degenerative disease or replace large damaged central nervous tissue remains an enormous challenge. Here, we developed a novel blood vessel-mimicking nanomaterial system by combining carboxylated cellulose nanofibers (CCN) with Matrigel to create biosafety scaffolds. These engineered scaffolds demonstrated a remarkable capacity to support the long-term growth over 300 days and functional maturation of neural organoids, enabling the development of centimeter-scale organoids without necrotic cores. CCN-engineered human spinal cord organoids (ChSOs) could self-elongate axon tracts, robustly form axon myelination and establish functional neural networks. Following transplantation, ChSOs demonstrated remarkable differentiation potential, generating both dorsal and ventral multiple subtype spinal cord neurons, which could migrate and sufficiently integrate with the host spinal cord tissue. Notably, these grafted ChSOs highly secrete axon guidance factor NTN1 enhancing axonogenesis and facilitate the restoration of sensory and motor functions of complete SCI in mice. These findings show that ChSOs offer a platform to study neural development and achieve functional spinal cord repair.