Neonatal and adult O4⁺ oligodendrocyte lineage cells display different growth factor responses and different gene expression patterns

Abstract

Oligodendrocytes are the myelinating cells of the central nervous system. While the CNS possesses the ability to repair demyelinating insults, in certain cases, such as the chronic lesions found in multiple sclerosis, remyelination fails. Cycling cells capable of becoming oligodendrocytes have been identified in both the developing and adult mammalian forebrain. Many studies have focused on differences in gene expression profiles as oligodendrocyte progenitors differentiate into myelinating oligodendrocytes by isolating cells at different developmental stages from animals at a single age. However, few have studied the differences that exist between the progenitors of the neonatal CNS and those of the adult CNS. This study examined the response of neonatal and adult O4+ cells to the growth factors PDGF-AA, bFGF, and IGF-1, and revealed marked differences. While adult cells readily differentiated in vitro, the majority of neonatal progenitors remained immature. Microarray analysis was used to examine differences between acutely isolated neonatal and adult progenitors further. Gene expression profiles found that the adult O4+ cells are more developmentally mature than neonatal cells. Neonatal cells expressed higher levels of genes involved in proliferation. Adult O4+ cells expressed higher levels of transcripts for genes involved in cell death and survival. Therefore, O4+ cells from the adult differ greatly from those of the neonate and the developmental stage of the animal models utilized must be taken into consideration when applying principles from neonatal systems to the adult.

Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process

“…However, these studies either introduced oncogenes into OPCs early in development, as in our previous work (14), or did not use lineage tracing tools (58,59). Thus, it is possible that the gliomagenic potential of OPCs could be dependent on their active perinatal state (65,66) and that adult OPCs may not be transformable because they rarely divide (9,(17)(18)(19)(20)(21). Our current study convincingly resolved this issue by introducing mutations specifically into adult OPCs and demonstrating their capacity for transformation.…”

“…Although all adult OPCs retain the ability to proliferate, they do so at a very slow rate, dividing only once in 36 d at P60 (60-d-old mice) compared with every 4 d at P6 (9,19). Furthermore, adult OPCs adopt a transcriptional program with much decreased expression of cell cycle genes (20,21), thus contributing to their infrequent proliferation. Reactivation of adult quiescent OPCs has been previously characterized in response to neuronal activity and to brain injury, both of which trigger proliferation followed by differentiation into myelinating oligodendrocytes (22)(23)(24), but never in the context of oncogenic mutations.…”

Regulation of Oligodendrocyte Differentiation: Relevance for Remyelination

“…First, OPC themselves may be less efficient in migration and differentiation. Indeed, the response to growth factors differs in adult OPC compared neonatal OPC possibly delaying the recruitment of OPC into lesion areas (Lin et al, 2009;Cui et al, 2010). Furthermore, histone deacetylates are less active in OPC of adult animals.…”

Myelin matters: proteomic insights into white matter disorders

“…Considering the scarcity of human biopsy and autopsy material, we believe that the emerging LC-MS-based methods show great promise for differential approaches to white matter disorders. Other systems biology techniques that have been applied in the myelin field mainly include transcriptome analyses of oligodendrocytes [70][71][72][73]. However, this information remains to be satisfactorily correlated with proteome data.…”