Injured Inflammatory Environment Overrides the TET2 Shaped Epigenetic Landscape of Pluripotent Stem Cell Derived Human Neural Stem Cells

Spinal cord injury creates an inflammatory microenvironment that regulates the capacity of transplanted human Neural Stem Cells (hNSC) to migrate, differentiate, and repair injury. Despite similarities in phenotype determined by gene expression and immunostaining, different hNSC populations do not necessarily have equivalent biological properties. This variation derives in part from the epigenetic landscape, specifically methylation (5mC) and hydroxymethylation (5hmC) in the hNSC genome, which could affect the response of hNSC to the injury microenvironment for mediating repair, especially after therapeutic transplantation.We describe a dramatic up-regulation of methylcytosine dioxygenase 2 (TET2) gene expression in undifferentiated hNSC derived from human embryonic stem cells (hES-NSC), and report that this is associated with hES-NSC competence for differentiation marker expression. TET2 protein catalyzes active demethylation; thus, TET2 upregulation could be a signature of pluripotent exit, shaping the epigenetic landscape in hES-NSC. We demonstrate that the inflammatory environment can override epigenetic programming in vitro and in vivo by directly modulating TET2 expression levels in hES-NSC to change cell fate.