Spinal cord extracellular matrix hydrogel enhances organoid maturation and functional regeneration after spinal cord injury.

Stem cell therapy has been widely studied as a promising treatment for spinal cord injury (SCI). However, a lack of functional scaffolds for stem cell therapy to address SCI leads to low therapeutic efficacy due to poor survival of transplanted cells. To address these challenges, this study aims to enhance regenerative potential of spinal cord organoids (SCOs) by employing extracellular matrix (ECM) recapitulating spinal cord-specific microenvironment. Decellularized spinal cord-derived ECM (ScEM) supports 3D culture for development, maturation, and functionality of human induced pluripotent stem cell-derived SCOs, comparable to standard organoid culture matrix such as Matrigel. Transplantation of SCOs using ScEM hydrogel promotes axonal regeneration with neovascularization in lesions, likely because of enhanced engraftment and integration of transplanted SCOs into defective tissues facilitated by ScEM. Accordingly, this approach induces early locomotor recovery of animals with SCI. These findings suggest that functional ECM scaffold capable of providing microenvironmental complexity of spinal cord can potentiate organoid-based therapeutics for SCI treatment.