Oligodendrocyte Fate Determination in Human Embryonic Stem Cells

Oligodendrocytes (OL) are cells of the glial lineage which play a critical role in the central nervous system (CNS) by producing the multilamellar protein, myelin. Oligodendrocytes extend processes which wrap around the axons of several neurons. This myelin sheath increases neuronal conduction by decreasing ion leakage and capacitance of the axonal membrane and increasing saltatory conduction. Damage to oligodendrocytes results in loss of myelin and consequent functional impairment due to loss or decay of neuronal conduction. Demyelination in the CNS is the hallmark of conditions such as spinal cord injury (SCI), transverse myelitis and multiple sclerosis – resulting in functional impairment across the sensory, motor and cognitive domains. Current research on treatment of SCI focuses on the implantation of oligodendrocyte progenitor cells (OPC) into the injured region to achieve remyelination of the spared axons and potentially repair the sensory and motor pathways. However, this approach requires a large and relatively pure population of OPCs, which are differentiated from other multipotent cell lineages. Human embryonic stem cells have been used in several studies for this purpose and hence, it is important to understand the molecular mechanisms regulating the differentiation of pluripotent hESCs to oligodendrocytes. Elucidation of such mechanisms may lead to the development of more efficient differentiation protocols and the derivation of cells with improved myelination potential for implantation in injured spinal cords. While the molecular basis for hESC differentiation into OL lineage cells is not completely understood, several recent studies have filled some of the gaps in our knowledge of the field. The journey from a pluripotent state to commitment to the OL fate is characterized by a complex interplay between genetic regulation and epigenetic modifiers such as histone modification, DNA methylation and microRNAs (miRNAs). Global miRNA expression profiling of OL differentiation from hESCs has revealed that a significant number of the differentially expressed miRNAs have targets hypothesized to be involved in myelination and OL development. Such studies are complemented by histone modification analyses in ESCs which show that specific histone acetyltransferases (HATs) and histone deacetylases (HDACs) are upor down-regulated during different time points in OL differentiation to