Suppressing CSPG/LAR/PTPr Axis Facilitates Neuronal Replacement and Synaptogenesis by Human Neural Precursor Grafts and Improves Recovery after Spinal Cord Injury

Abstract

Traumatic spinal cord injury (SCI) is a leading cause of permanent neurologic disabilities in young adults. Functional impairments after SCI are substantially attributed to the progressive neurodegeneration. However, regeneration of spinal-specific neurons and circuit re-assembly remain challenging in the dysregulated milieu of SCI because of impaired neurogenesis and neuronal maturation by neural precursor cells (NPCs) spontaneously or in cell-based strategies. The extrinsic mechanisms that regulate neuronal differentiation and synaptogenesis in SCI are poorly understood. Here, we perform extensive in vitro and in vivo studies to unravel that SCI-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) impedes neurogenesis of NPCs through co-activation of two receptor protein tyrosine phosphatases, LAR and PTPr. In adult female rats with SCI, systemic co-inhibition of LAR and PTPr promotes regeneration of motoneurons and spinal interneurons by engrafted human directly reprogramed caudalized NPCs (drNPC-O2) and fosters their morphologic maturity and synaptic connectivity within the host neural network that culminate in improved recovery of locomotion and sensorimotor integration. Our transcriptomic analysis of engrafted human NPCs in the injured spinal cord confirmed that inhibition of CSPG receptors activates a comprehensive program of gene expression in NPCs that can support neuronal differentiation, maturation, morphologic complexity, signal transmission, synaptic plasticity, and behavioral improvement after SCI. We uncovered that CSPG/LAR/PTPr axis suppresses neuronal differentiation in part by blocking Wnt/b-Catenin pathway. Taken together, we provide the first evidence that CSPGs/LAR/PTPr axis restricts neurogenesis and synaptic integration of new neurons in NPC cellular therapies for SCI. We propose targeting LAR and PTPr receptors offers a promising clinically-feasible adjunct treatment to optimize the efficacy and neurologic benefits of ongoing NPC-based clinical trials for SCI.