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Oligodendrocyte progenitor cell

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Oligodendrocyte precursor cell
Identifiers
MeSHD000073637
THH2.00.06.2.01007
Anatomical terms of neuroanatomy

Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, are a subtype of glia in the central nervous system.[1] They are precursors to oligodendrocytes and may also be able to differentiate into neurons and astrocytes. Differentiated oligodendrocytes support axons and provide electrical insulation in the form of a myelin sheath, enabling faster action potential propagation and high fidelity transmission without a need for an increase in axonal diameter.[2] The loss or lack of OPCs, and the related lack of differentiated oligodendrocytes is associated with a loss of myelination and subsequent impairment of neurological functions.[3]

Description

OPCs are a subtype of glia cells in the central nervous system, characterised by expression of the proteoglycan CSPG4 and PDGFRA.[4] OPCs encompass approximately 3-4% of cells in the grey matter and 7-8% in white matter, making them the fourth largest group of glia after astrocytes, microglia and oligodendrocytes.[5] In white matter, OPCs are found along unmyelinated axons [6] as well as along myelinated axons, engulfing nodes of Ranvier.[7]


Function

The primary function of OPCs is to serve as precursor for oligodendrocytes as well as some protoplasmic astrocytes in grey matter.[8] Whereas some earlier studies have suggested that OPCs can generate cortical neurons, more recent studies have refuted these findings.[9]

Development

OPCs originate from the neuroepithelium of the spine and migrate to other areas of the brain.[10] OPCs are highly proliferative and migratory bipolar cells[11] They differentiate into the less moble, pro-oligodendrocytes which further differentiate into oligodendrocytes, a process characterized by the emergence of the expression of myelin basic protein (MBP), proteolipid protein (PLP), or myelin-associated glycoprotein (MAG).[11] Following terminal differentiation in vivo, mature oligodendrocytes wrap around and myelinate axons. In vitro, oligodendrocytes create an extensive network of myelin-like sheets. The process of [differentiation] can be observed both through morphological changes and cell surface markers specific to the discrete stage of differentiation, though the signals for differentiation are unknown.[12]

Differentiation of OPCs into oligodendrocytes involves massive reorganization of cytoskeleton proteins ultimately resulting in increased cell branching and lamella extension, allowing oligodendrocytes to myelinate multiple axons.[11] Several distinct pathways have been identified as the cause of oligodendrocyte branching, but their specific contributions have yet to be elucidated and the process by which oligodendocytes extend and wrap around multiple axons remains poorly understood.[11]

Oligodendrocytes in Disease

A plethora of central nervous system diseases cause damage to oligodendrocytes resulting in demyelination and leading to neurological disability through the resulting loss of conduction speed. Myelin diseases can be categorized into two broad types: those that cause targeted chronic damage to oligodendrocytes specifically, such as in multiple sclerosis, and those in which the oligodendocyte is injured as a result of non-specific disease or damage, as is the case in ischemia or trauma.

In either case, normal conduction is no longer possible via the affected pathways resulting in plastic change of the chronically demylinated axon. Normally clustered at the nodes of Ranvier, sodium channels are redistributed more evenly across the axon.[13] This redistribution has important functional consequences: conduction across the axon is re-established, but the speed of conduction is reduced. Normal conduction speed can be restored with remyelination.[13]

Spontaneous remyelination has been observed in the human central nervous system, though remyelinated axons display myelin that is disproportionately small compared to the normal myelin on an axon of similar diameter.[14] Functionally, conduction speed, and therefore neurological function, is fully restored by remyelination, though it should be noted that the restoration of conduction velocity occurs before full remyelination.[15]

Endogenous Remyelination

Spontaneous myelin repair was first observed in feline models,[16] but was later discovered to occur in the human central nervous system as well, specifically in cases of multiple sclerosis.[17] Spontaneous myelin repair does not result in morphologically normal oligodendrocytes and is associated with thinner myelin compared to axonal diameter than normal myelin.[14] Despite morphological abnormalities, however, remyelination does restore normal conduction.[15] In addition, spontaneous remyelination does not appear to be a rare event, at least in the case of multiple sclerosis. Studies of multiple sclerosis lesions have reported the average extent of remyelination to be as high as 47%,[18] and comparative studies of cortical lesions reported a greater proportion of remyelination in the cortex as opposed to white matter lesions.[17]

Cell Types Involved

Mature oligodendrocytes, however, are unlikely to contribute to spontaneous remyelination even if they survive the original demyelinating injury.[19] New oligodendrocytes have been observed in areas of myelin damage, though the source of these new cells is not entirely clear. One possibility is that mature oligodendrocytes from uninjured areas migrate to the site of injury and re-engage in myelination, though this is considered to be an unlikely scenario as the transplantation of mature human oligodendrocytes achieve minimal myelin formation in the demyelinated rodent central nervous system. Another possibility is that mature oligodendrocytes de-differentiate into proliferative oligodendrocyte progenitors, that are then able to proliferate and remyelinate though there is little experimental support for this view.

Source of New Oligodendrocytes

There is evidence, however, to suggest that the source of these new oligodendrocytes is proliferative adult oligodendrocyte precursor cells. Such cells have been demonstrated to exist in the adult rodent central nervous system[20] as well as the human central nervous system.[21] These oligodendrocyte precursor cells appear to play a major role in remyelination and are, unlike mature oligodendrocytes, able to cause extensive remyelination after transplantation into areas of myelin damage.[22] The role of these cells when there is no local demyelination, however, is still very much under investigation and the fact that oligodendrocyte progenitors exhibit electrophysiological properties related to the expression of a range of glutamate receptors allowing communication with the neuron-axon unit suggests that oligodendrocyte progenitors are likely to have additional functions.[23]

Other Factors Influencing Remyelination

Chronic demyelination may[24] or may not[25] inhibit the ability of the central nervous system to remyelinate. In either case, the observation of accumulating neurological disability in multiple sclerosis patients seems to suggest that any endogenous remyelination mechanism is overwhelmed with the extent of demyelination or fails in some other way. Several mechanisms have been proposes by which the spontaneous remyelination mechanism could fail.

The observation of oligodendrocyte progenitors in multiple sclerosis lesions that have not remyelinated has led to the hypothesis that the differentiation of these progenitors has been inhibited. One proposed mechanism involves the accumulation of myelin debris at the axon, suggesting that the inflammatory environment may be conducive to remyelination, as does the release of growth factors by inflammatory cells and activated microglia.[26] Alternatively, the accumulation of glycosaminoglycan hyaluronan at the site of the lesion, inhibiting the ability of oligodendrocyte progenitors to differentiate into mature oligodendrocytes and the release of oligodendrocyte progenitor-specific antibodies by chronically demyelinated axons have been implicated as the reason remyelination is not more extensive.[27] Other proposed mechanisms posit that oligodendrocyte progenitor migration is inhibited by either molecules expressed by chronically demyelinated axons or the accumulation of unreactive astrocytes in multiple sclerosis lesions.[27]

Transplantation

Apart from spontaneous remyelination, therapeutic myelin repair may be possible, though the type and source of cells for transplant is still unclear. Schwann Cells have shown to be successful in remyelinating the spinal cord of the rat,[20] mouse,[28] and macaque,[29] though immortalized rodent Schwann cells show a tendency to form tumors when transplanted.[30] In addition, transplanted olfactory myelinating cells are being explored as possible therapeutic remyelinating agents.[20]

Oligodendrocyte progenitor transplants have been demonstrated to contribute to remyelination, but it is difficult to maintain such cells in reasonable concentrations at high puritiy. Finding a source for these cells, however, is impractical at the moment. Should adult cells be used for transplantation, a brain biopsy would be required for every patient, added to the risk of immune rejection. Embryonically derived stem cells have been demonstrated, to carry out remyelination under laboratory conditions, but carry ethical implications. Adult central nervous system stem cells have also been shown to generate myelinating oligodendrocytes, but are not readily accessible.[31]

Even if a viable source of oligodendrocyte progenitors were found, identifying and monitoring the outcome of remyelination remains difficult though multimodal measures of conduction velocity and emerging magnetic resonance imaging techniques offer improved sensitivity verses other imaging methods.[32] In addition, the interaction between transplanted cells and immune cells has yet to be fully characterized as does the effect of inflammatory immune cells on remyelination. If the failure of the endogenous remyelination mechanism is due to an unfavorable differentiation environment, then this will have to be addressed prior to any transplantation attempt.

References

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