Premyelinating Oligodendrocytes: Mechanisms Underlying Cell Survival and Integration

Abstract

In the central nervous system, oligodendrocytes produce myelin sheaths that enwrap neuronal axons to provide trophic support and increase conduction velocity. New oligodendrocytes are produced throughout life through a process referred to as oligodendrogenesis. Oligodendrogenesis consists of three canonical stages: the oligodendrocyte precursor cell (OPC), the premyelinating oligodendrocyte (preOL), and the mature oligodendrocyte (OL). However, the generation of oligodendrocytes is inherently an inefficient process. Following precursor differentiation, a majority of premyelinating oligodendrocytes are lost, likely due to apoptosis. If premyelinating oligodendrocytes progress through this survival checkpoint, they generate new myelinating oligodendrocytes in a process we have termed integration. In this review, we will explore the intrinsic and extrinsic signaling pathways that influence preOL survival and integration by examining the intrinsic apoptotic pathways, metabolic demands, and the interactions between neurons, astrocytes, microglia, and premyelinating oligodendrocytes. Additionally, we will discuss similarities between the maturation of newly generated neurons and premyelinating oligodendrocytes. Finally, we will consider how increasing survival and integration of preOLs has the potential to increase remyelination in multiple sclerosis. Deepening our understanding of premyelinating oligodendrocyte biology may open the door for new treatments for demyelinating disease and will help paint a clearer picture of how new oligodendrocytes are produced throughout life to facilitate brain function.

Ambient RNA analysis reveals misinterpreted and masked cell types in brain single-nuclei datasets

“…For a definitive answer, we then tested two non-oligodendrocyte lineage cell types, AST and MIC (microglia), which also revealed similar ‘transitioning cells’ that were highly enriched in both ambient RNA and immature oligodendrocyte markers and were effectively removed by our ambient RNA removal process (Extended Figure 5E-G) . Given that immature oligodendrocytes also lack known markers of committed OPCs (COPs) or premyelinating oligodendrocytes (Pre-OL) (e.g BCAS1 , ENPP6 , GPR17 31 ) (Extended Figure 5H) , our results indicate that cells previously annotated as immature oligodendrocytes are not transitioning cells but rather glia with high contamination of neuronal ambient RNA.…”

Age and Alzheimer’s Disease-Related Oligodendrocyte Changes in Hippocampal Subregions

“…Thus, all three macroglial cell populations in the hippocampus may follow distinct patterns of number change with age. Although astrocytes and microglia play critical roles in the early OL development and survival throughout the CNS ( Domingues et al, 2016 ), OL density changes in local brain regions at later ages may be subjected to additional regulatory mechanisms, including circuit-specific neuronal activities ( Kougioumtzidou et al, 2017 ; Hughes and Stockton, 2021 ). It is unclear whether neuronal activity controls astrocyte density.…”

Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination

“…Antibodies to other viruses have been associated with increased MS conversion and relapse including human herpes virus 6 (HHV-6) [48]. It is believed that the induction of demyelination in the brain and spinal cord in MS may be initiated by excess innate and myelin-specific autoimmune activation mechanisms that are sensitive to chronic viral infections and gut microbiome status [49] and perpetuated by the loss of oligodendrocytes and their progenitors through either perforin-mediated lysis [50][51][52] or apoptotic cell death [53].…”