Targeting SOX9 expression in human neural stem cells is a therapeutic strategy for spinal cord injury

Abstract

Neural stem cells (NSCs) exist in both embryonic and adult neural tissues and are characterized by their self-renewal capacity and multipotency that contribute to the formation of neurons, oligodendrocytes and astrocytes in the vertebrate central nervous system (CNS). The tremendous therapeutic potential of NSCs to treat CNS diseases and injuries has provoked intensive study in the regulation of their formation and differentiation into specific neural lineage. Previous studies showed that SOX9 is crucial for the formation and maintenance of NSCs as well as inhibition of neuronal differentiation in both mouse and chick CNS. Whether SOX9 plays similar roles in human NSCs (hNSCs) remains unknown. Here, we demonstrate that high SOX9 expression is associated with acquisition of hNSC fate. Targeting SOX9 expression by shRNA does not affect hNSCs formation, but promotes precocious differentiation into motor neurons compared to scramble control. Gene expression profiling studies in SOX9 knockdown (SOX9 KD) hNSCs reveal upregulated expression of sonic hedgehog and its downstream effectors that are known to promote spinal neuron formation. Most importantly, transplantation of SOX9 KD hNSCs into the injured rodent spinal cord results in robust differentiation into motor neurons without forming glial scar at the lesion site and also improved locomotion capabilities. Altogether, our findings reveal a distinct, but conserved, role of SOX9 in NSCs formation and the onset of neuronal differentiation between human and other vertebrate species, respectively. Targeting SOX9 expression in hNSCs could be a viable therapeutic strategy for spinal cord injury.