Circuit re-construction after traumatic spinal cord injury by cellular and pharmacological approaches

Abstract

Extensive neuronal loss, progressive neurodegeneration, and circuit impairment are the key pathological features of spinal cord injury (SCI). The intrinsic capacity of the injured spinal cord to replenish damaged neurons and re-assemble the disrupted spinal circuitry is restricted. Transplantation of exogenous neural precursor cells (NPCs) has shown promise to structurally repair the injured spinal network. However, proper maturation and integration of newly generated neurons from NPC graft within the host spinal circuit has remained challenging. Here, in adult female Sprague Dawley rats, we demonstrate that blockade of CSPG/LAR/PTP-σ axis in combination with neuromodulation by activation of 5-HT_1/2/7 receptors augment the generation of spinal cord-specific neurons by NPC grafts and supports the maturity and functional connectivity of NPC-derived neurons with the host local spinal network as well as major descending motor pathways that culminate in recovery of locomotion and sensorimotor integration. Taken together, this novel cellular and pharmacological approach facilitates functional restoration of neural networks within the damaged spinal circuitry that addresses a critical gap in cell-based repair strategies for SCI.

Significance of Statement Engraftment of neural precursor cells (NPCs) is a promising therapeutic approach to restore the damaged circuitry after spinal cord injury (SCI). However, their differentiation toward spinal interneurons and motoneurons, and their functional integration and connectivity to the host local and supraspinal network are limited. Here, we demonstrate that blocking chondroitin sulfate proteoglycans (CSPG)/LAR/PTP-σ axis combined with activation of serotonin receptors 5-HT_1/2/7 significantly increases differentiation of transplanted NPCs into spinal cord specific neurons and enhances synaptic connectivity of NPC-derived neurons with the host spinal circuitry. These findings provide a translationally relevant approach to re-assemble the disrupted network after SCI.