Characterization and application of patient derived Glial Enriched Progenitors to repair functional deficits due to white matter stroke.

Subcortical white matter stroke (WMS) accounts for up to 30% of all stroke events. WMS damages astrocytes, axons, oligodendrocytes, and myelin. We hypothesized that an astrocytic therapy would be ideally suited for brain repair after WMS. We characterized the molecular profile, epigenetic patterns and in vivo tissue repair activity of a novel glial enriched progentior cell differentiated from human induced pluripotent stem cells (hiPSCs). hiPSC-GEPs are derived from hiPSCs with an experimental manipulation of HIF activity by brief treatment with a prolyl hydroxylase inhibitor. This treatment permanently biased these cells toward an immature astrocyte fate. hiPSC-GEPs transplanted into the brain in the subacute period after WMS migrate widely, mature into astrocytes and induced endogenous oligodendrocyte precursor proliferation and re-myelination. hiPSC-GEPs enhanced motor recovery compared to other hiPSC-differentiated cell types. This approach establishes a hiPSC-derived product with easy scale-up capabilities and efficacy in a common and untreatable brain disease. Overall design: Human neural progenitors were stimulated with low oxygen or drugs that increase HIF activity, and then processed to determine where H3K27ac and H3K9me3 histone marks are applied throughout the genome with ChIP_SEQ