Xingxing Wang, Yale University School of Medicine, New Haven, USA

Combination of Nogo Receptor Intervention and Neural Stem Cell Transplantation for Spinal Cord injury

Funded in: 2014, 2015, 2016

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Problem: Poor axon regeneration after SCI due to weak ability of axons to regenerate and to glial scar and cystic cavity

Target: Neural Stem Cell grafting and blocking of growth inhibiting factors by Nogo Receptor 1 decoy treatment

Goal: Combinatorial therapy for neural repair and locomotor recovery after spinal cord contusion.

Spinal cord injury (SCI) results in permanent significant neurological deficits. The neurological deficits post injury are mainly due to the interruption of axonal connectivity between descending neurons from the brain and surviving neurons below the injury site, and severed axons do not regenerate. Research demonstrates that central nervous system (CNS) axons are able to regenerate in a permissive environment. The glial scar and cystic cavity within the lesion represent a significant physical and chemical barrier to axonal regeneration. Myelin-associated inhibitors limit the axon regeneration after injury.

The myelin inhibition from three myelin-derived molecules Nogo-A, MAG and OMgp is mediated by NgR1 which can be efficiently blocked by soluble NgR1 decoy treatment. In previous studies NgR(310)ecto-Fc treatment promoted both axonal growth and locomotor recovery after rat spinal contusion. Significantly greater numbers of cortical spinal tract (CST) fibers were present rostral to the injury, but no CST fibers were observed caudal to the lesion site.

Neural stem cell (NSC) transplantation therapy offers a permissive environment for axonal regeneration and plasticity by providing a bridge for axonal growth in the lesion area.

In this study, both will be applied, NSCs grafting and NgR1 decoy treatment in a rat spinal contusion model, which very closely mimics human spinal cord injury. The hypothesis is that this combinatorial treatment will synergistically promote axonal growth of endogenous survived neurons and integration of grafted cells in the host tissue, thus further improving functional recovery after SCI. The goal of this proposal is to develop a combinatorial therapy for more extensive neural repair and locomotor recovery after spinal cord contusion.