Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

Abstract

Apoptosis plays a crucial role in brain development by ensuring that only appropriately growing, migrating, and synapse-forming neurons and their associated glial cells survive. This process involves an intimate relationship between cell-cell interactions and developmental cues and is further impacted by environmental stress during neurogenesis and disease. Oligodendrocytes (OLs), the major myelin-forming cells in the central nervous system, largely form after this wave of neurogenesis but also show a selective vulnerability to cell death stimuli depending on their stage of development. This can affect not only embryonic and early postnatal brain formation but also the response to demyelinating pathologies. In the present review, we discuss the stagespecific sensitivity of OL lineage cells to damage-induced death and how this might impact myelin survival and regeneration during injury or disease. Apoptosis is a major form of programmed cell death required for the normal development of metazoan tissues, including the brain. 1 During embryonic development of the brain, many more cells than ultimately needed are generated and then selection occurs, resulting in the apoptotic depletion of the surplus cells. The importance of the apoptotic pathway in early brain development has been demonstrated by the targeted deletion in mice of the death-specific cysteine proteases caspase-3 or caspase-9, or of the co-activator Apaf-1, all of which cause severe brain overgrowth and perinatal death. 2,3 In the adult brain, 90% of the cells belong to the glial lineage, which includes oligodendrocytes (OLs), astrocytes and microglia. The glia ensures proper development, function and repair of the neuronal network. This is possible through continuous cross-talk between the glia and neurons mediated by neurotransmitters, cytokines, growth and trophic factor secretion and signaling in a reciprocal manner. [4][5][6][7] In the central nervous system (CNS), OLs are responsible for axon myelination, which insulates the electrical signals transmitted between neurons. OL and neuron development is tightly regulated and the myelin sheath is constructed only when OLs reach maturity and neurons have grown appropriately. In response to injury or during the course of neurological diseases, the neuron-glia network can be replenished to some extent but the degree of repair is dependent on the developmental stage of the OL. This complexity is compounded by the differential sensitivity of OL lineage cells to apoptotic stimuli. In the present review, we will first briefly examine the stages of differentiation of OL cells and then discuss several diseases that are impacted by OL apoptosis, noting how the stage of cell differentiation governs the sensitivity to apoptosis. Defined Stages of OL DevelopmentOligodendrocyte development can be divided into four distinct stages according to the temporal expression of cell surface markers and morphology (Table 1). 8 In the first stage, OL progenitor cells (OPCs) originate from the neuroepithelium of the ventricul...

Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target

“…It is possible that exposure to A␤ disrupts the delicate homeostasis maintained in these cells, thereby leading to apoptotic cell death. 42 Our in vitro experiments in immature and mature mOP cells did not reveal any stage-specific differences in A␤ vulnerability. However, in vivo, where contributing factors relating to microglia-derived reactive oxygen species and cytokines, such as tumor necrosis factor-␣ (TNF-␣) are present, the selective impact on mature myelinating oligodendrocytes could be greater.…”

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

“…The increased vulnerability of ATM-deficient differentiating oligodendrocytes to oxidative stress could reflect a more critical role of the antioxidant defence in these cells, which contain high amounts of iron than can evoke radical formation. 27 Although a substantial cell death involving the activation of caspases and cleavage of PARP accompanied the differentiation of ihNSCs, this apoptotic activity was less pronounced in shATM. Although this could reflect a unique behavior of our cell model, it cannot be excluded that it might reflect a more physiological phenomenon linked to neurogenesis.…”

“…The expression of these oligodendrocyte lineage markers in a large proportion of our neural stem cells is in agreement with the findings in murine neurospheres. 26 The flow cytometry analysis showed also a faint expression of CNPase, a marker of immature oligodendrocytes, 27 and virtual absence of GalC staining (Supplementary Figure S5). The regulation during differentiation of Olig2 and PDGFR-a assessed on western blots showed a modest reduction in Olig2 levels between D0 and D3 in shATM relative to shATM, and a marked drop in PDGFR-a levels at D10, more effective in shATM than shCon, particularly at D17 (Supplementary Figure S6).…”

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

“…Cultured OPCs differentiate into myelin-basic-protein expressing mature oligodendrocytes step-by-step, and these oligodendrocyte lineage cells can be categorized by expression of specific cell-surface receptors, cell morphology, and proliferative/motility responses. 17,19 Thus far, several soluble factors (e.g., growth factors, hormones, and cytokines) have been identified to regulate the OPC-to-oligodendrocyte maturation, and in vitro co-culture or media-transfer experiments have shown how brain cells contribute to the OPC maturation steps in vitro (Table 3).…”