Elucidating the roles of SOX9 in human neural stem cells.

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 generation of three major cell types in the vertebrate central nervous system (CNS): neurons, oligodendrocytes and astrocytes. The tremendous therapeutic potential of NSCs to treat the neurodegenerative diseases and CNS injuries has provoked intensive study in the regulation of their formation and differentiation into specific neural lineage. Previous studies showed that SOX9, a member of SOXE transcription factors family, is crucial for the formation and maintenance of NSCs in both mouse and chick CNS, as well as directing cell fate switch between neurons and glia. 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 did not affect hNSCs formation, but promotes self-renewal capacity of hNSCs which acquire early neuronal fate commitment when cultured in permissive conditions compared to scramble shRNA-treated hNSPs. Gene expression analysis reveal upregulation of proneural genes in SOX9 knockdown hNSPs that explain accelerated neuronal differentiation. Altogether our results differ from previous reports that reveal a putative novel role of SOX9 in controlling the degree of self-renewal capacity and neuronal differentiation, highlighting functional differences of SOX9 in NSPs between human and other vertebrate species.