| Summary: | Summary: Impaired human oligodendrocyte progenitor cell (hOPC) differentiation likely contributes to failed remyelination in multiple sclerosis. The characterization of molecular pathways that regulate hOPC differentiation will provide means to induce remyelination. In this study, we determined the gene expression profile of PDGFαR+ hOPCs during initial oligodendrocyte commitment. Weighted gene coexpression network analysis was used to define progenitor and differentiation-specific gene expression modules and functionally important hub genes. These modules were compared with rodent OPC and oligodendrocyte data to determine the extent of species conservation. These analyses identified G-protein β4 (GNB4), which was associated with hOPC commitment. Lentiviral GNB4 overexpression rapidly induced human oligodendrocyte differentiation. Following xenograft in hypomyelinating shiverer/rag2 mice, GNB4 overexpression augmented myelin synthesis and the ability of hOPCs to ensheath host axons, establishing GNB4 as functionally important in human myelination. As such, network analysis of hOPC gene expression accurately predicts genes that influence human oligodendrocyte differentiation in vivo. : Oligodendrocyte progenitor cell differentiation requires the coordinated regulation of many genes. Sim and colleagues capture the transcriptional profile during human primary oligodendrocyte specification. Using WGCNA and cross-species dataset comparisons, they identify jointly regulated genes, conserved across human and rodent species. Targeting highly regulated genes, they show that G-protein subunit β4 expression accelerates human oligodendrocyte differentiation. Keywords: oligodendrocyte progenitor, species conservation
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