Specific Derivative Retains Embryonic Chromatin Plasticity for Scale-Up CNS Regeneration

Background: Pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the therapeutic potential of hESC derivatives has been hindered by generating neuronal cells from pluripotent cells through uncontrollable and inefficient multi-lineage differentiation. Previously, we used a defined platform to identify retinoic acid as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger uniform neuronal lineage-specific progression to human neuronal progenitors (hESC-I hNuPs) and neurons (hESC-I hNus) in the developing CNS with high efficiency. Methods: Having achieved uniformly conversion of pluripotent hESCs to a neuronal lineage, in this study, the expression and intracellular distribution patterns of a set of chromatin modifiers in hESC-I hNuPs were examined and compared to the two prototypical neuroepithelial-like human neural stem cells (hNSCs) either derived from hESCs or isolated directly from the human fetal neuroectoderm in vivo. Results: These hESC-I hNuPs expressed high levels of active chromatin modifiers, including acetylated histone H3 and H4, HDAC1, Brg-1, and hSNF2H, retaining an embryonic acetylated globally active chromatin state. Consistent with this observation, several repressive chromatin remodeling factors regulating histone H3K9 methylation, including SIRT1