Engineered thoracic spinal cord organoids for transplantation after spinal cord injury

Stem-cell-based neural tissue engineering and spinal cord organoids show promises for spinal cord injury repair. However, the native spinal cord presents cell heterogeneity and a stereotypical spatial structure that makes difficult their recapitulation within an organoid architecture, which requires an assembly encompassing cellular composition, segmental organization and dorsoventral features. Here we engineer a thoracic vertebral segment-specific spinal cord organoid (enTsOrg) model that can precisely match the transplantation site, establish synaptic connections and enhance in vivo neuroelectric conduction. The organoids are generated from fibroblasts-derived induced pluripotent stem cells and a layered double-hydroxide matrix in a basement membrane hydrogel (Matrigel). Grafted in a spinal cord injury mouse model, enTsOrg presents advanced maturation, functionalization and organized distribution of critical neuronal subtypes with thoracic segmental heterogeneity, including various motor neuron and interneuron subtypes, that serve essentially to restore motor functions. Transplantation of enTsOrg can restructure neural circuits in paralysed animals and restore hind-limb motor function. The robust neurological function and therapeutic efficacy of enTsOrg highlight a potential avenue for organoid designing for specific anatomical regions in neurological injury treatments.