Injury and Therapy in a Human Spinal Cord Organoid [RNA-seq]

Damage to the spinal cord, which can lead to irreversible paralysis and loss of sensory function, is among the most devastating injuries suffered by humans. A significant effort has been made over the past few decades to find therapies to treat spinal cord injury (SCI) but translation of pre-clinical work remains elusive. Experimental access to human spinal cord tissue is therefore critical to accelerate discovery of effective SCI therapies. Thus, availability of the organ mimics known as organoids offers great potential for this important objective. We report here on the development of two human organoid injury models to simulate SCI in vitro, using as a therapy bioactive supramolecular assemblies of peptide amphiphiles. The system tested here has been recently shown to be highly effective at reversing paralysis in an acute murine model following severe SCI. The models use either a laceration of the organoid with a scalpel or a compressive contusion commonly used in preclinical models. We found that both injuries result in immediate neuronal death and interestingly generate glial scar-like tissue. Exposure of the injured organoids to the pre-clinical therapy validated in vivo avoided formation of the scar-like tissue and promoted significant axonal regeneration. Furthermore, in the absence of injury, we directly observed the activation of the developmental program that extends neurites as a result of the therapy. Our observations indicate that injury models on human organoids could accelerate the discovery of therapies to treat spinal cord injury and possibly damage of other central nervous system tissues due to trauma or disease.