Oligodendrocyte progenitor cell

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of

OPCs are present throughout the brain, including the hippocampus and in all layers of the neocortex.^[7] They distribute themselves and achieve a relatively even distribution through active self-repulsion.^[5][8] OPCs constantly survey their surroundings through actively extending and retracting processes that have been termed growth cone like processes.^[9] Death or differentiation of an OPC is rapidly followed by migration or local proliferation of a neighboring cell to replace it.

In white matter, OPCs are found along unmyelinated axons

OPCs receive synaptic contacts onto their processes from both glutamatergic^[14] and GABAergic neurons.^[1][15] OPCs receive preferred somatic contacts from fast-spiking GABAergic neurons, while non-fast spiking interneurons have a preference for contacting the processes.^[16] These inhibitory connections (in mice) occur mainly during a specific period in development, from postnatal day 8 till postnatal day 13.

Development

OPCs first appear during embryonic

As development progresses, second and third waves of OPCs originate from Gsh2-expressing cells in the lateral and caudal ganglionic eminences and generate the majority of adult oligodendrocytes.^[22] After the committed progenitor cells exit the germinal zones, they migrate and proliferate locally to eventually occupy the entire CNS parenchyma. OPCs are highly proliferative, migratory, and have bipolar morphology.^[28]

OPCs continue to exist in both white and grey matter in the adult brain and maintain their population through self-renewal.

Typically beginning in

The possibility and in vivo relevance of OPC differentiation into astrocytes or neurons are highly debated.[1] Using Cre-Lox recombination-mediated genetic fate mapping, several labs have reported the fate of OPCs using different Cre driver and reporter mouse lines.^[40] It is generally held that OPCs predominantly generate oligodendrocytes, and the rate at which they generate oligodendrocytes declines with age and is greater in white matter than in grey matter. Up to 30% of the oligodendrocytes that exist in the adult corpus callosum are generated de novo from OPCs over a period of 2 months. It is not known whether all OPCs eventually generate oligodendrocytes while self-renewing the population, or whether some remain as OPCs throughout the life of the animal and never differentiate into oligodendrocytes.^[41]

OPCs may retain the ability to differentiate into astrocytes into adulthood.^[42][43] Using NG2-Cre mice, it was shown that OPCs in the prenatal and perinatal grey matter of the ventral forebrain and spinal cord generate protoplasmic type II astrocytes in addition to oligodendrocytes. However, contrary to the prediction from optic nerve cultures, OPCs in white matter do not generate astrocytes. When the oligodendrocyte transcription factor Olig2 is deleted specifically in OPCs, there is a region- and age-dependent switch in the fate of OPCs from oligodendrocytes to astrocytes.^[44]

Whereas some studies suggested that OPCs can generate

As implied by their name, OPCs were long held to function purely as progenitors to oligodendrocytes. Their role as a progenitor cell type has since expanded to include both oligodendrocytes and some protoplasmic type II astrocytes in grey matter.^[43] Later, additional functions were suggested.

Adult myelination

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Remyelination

Spontaneous myelin repair was first observed in cat models.^[49] It was later discovered to occur in the human CNS as well, specifically in cases of multiple sclerosis (MS).^[50] Spontaneous myelin repair does not result in morphologically normal oligodendrocytes and is associated with thinner myelin compared to axonal diameter than normal myelin.^[51] Despite morphological abnormalities, however, remyelination does restore normal conduction.^[52] In addition, spontaneous remyelination does not appear to be rare, at least in the case of MS. Studies of MS lesions reported the average extent of remyelination as high as 47%.^[53] Comparative studies of cortical lesions reported a greater proportion of remyelination in the cortex as opposed to white matter lesions.^[50]

OPCs retain the ability to proliferate in adulthood and comprise 70–90% of the proliferating cell population in the mature CNS.

Despite OPCs' potential to give rise to myelinating oligodendrocytes, complete myelin regeneration is rarely observed clinically or in chronic experimental models. Possible explanations for remyelination failure include depletion of OPCs over time, failure to recruit OPCs to the demyelinated lesion, and failure of recruited OPCs to differentiate into mature oligodendrocytes^[58] (reviewed in^[59][60][61]). In fresh MS lesions, clusters of HNK-1+ oligodendrocytes have been observed,^[62] which suggests that under favorable conditions OPCs expand around demyelinated lesions and generate new oligodendrocytes. In chronic MS lesions where remyelination is incomplete, there is evidence that there are oligodendrocytes with processes extending toward demyelinated axons, but they do not seem to be able to generate new myelin.^[63] The mechanisms that regulate differentiation of OPCs into myelinating oligodendrocytes are an active area of research.

Another unanswered question is whether the OPC pool eventually becomes depleted after it is used to generate remyelinating cells. Clonal analysis of isolated OPCs in the normal mouse forebrain suggests that in the adult, most clones originating from single OPCs consist of either a heterogeneous population containing both oligodendrocytes and OPCs or a homogeneous population consisting exclusively of OPCs, suggesting that OPCs in the adult CNS are able to self-renew and are not depleted under normal conditions.^[64] However, it is not known whether this dynamic is altered in response to demyelinating lesions.

Neuron–OPC interactions

Node of Ranvier

OPCs extend their processes to the nodes of Ranvier^[11] and together with astrocyte processes make up the nodal glial complex. Since the nodes of Ranvier contain a high density of voltage-dependent sodium channels and allow regenerative action potentials to be generated, it is speculated that this location allows OPCs to sense and possibly respond to neuronal activity.

Neuromodulation

OPCs synthesize the

OPCs can undergo cell division while maintaining synaptic inputs from neurons.^[70] These observations suggest that cells that receive neuronal synaptic inputs and those that differentiate into oligodendrocytes are not mutually exclusive cell populations but that the same population of OPCs can receive synaptic inputs and generate myelinating oligodendrocytes. However, OPCs appear to lose their ability to respond to synaptic inputs from neurons as they differentiate into mature oligodendrocytes.^[71][72] The functional significance of the neuron-OPC synapses remains to be elucidated.

Immunomodulation

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OPCs may participate in both initiation and resolution of immune responses to disease or injury. They are highly responsive to injury, undergo a morphological activation similar to that of astrocytes and microglia, and may contribute to

Clinical significance

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Transplantation of OPCs has been considered as a possible treatment for neurological diseases which cause demyelination. However, it is difficult to generate a suitable number of quality cells for clinical use. Finding a source for these cells remains impractical as of 2016. Should adult cells be used for transplantation, a brain biopsy would be required for each patient, adding to the risk of immune rejection. Embryonically derived stem cells have been demonstrated to carry out remyelination under laboratory conditions, but some religious groups are opposed to their use.^{[citation needed]} Adult central nervous system stem cells have also been shown to generate myelinating oligodendrocytes, but are not readily accessible.^[77]

Even if a viable source of OPCs 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 versus other imaging methods.^[78] In addition, the interaction between transplanted cells and immune cells and the effect of inflammatory immune cells on remyelination have yet to be fully characterized. If the failure of endogenous remyelination is due to an unfavorable differentiation environment, then this will have to be addressed prior to transplantation.^{[citation needed]}

History

It had been known since the early 1900s that astrocytes, oligodendrocytes, and microglia make up the major glial cell populations in the mammalian CNS. The presence of another glial cell population had escaped recognition because of the lack of a suitable marker to identify them in tissue sections. The notion that there exists a population of glial progenitor cells in the developing and mature CNS began to be entertained in the late 1980s by several independent groups. In one series of studies on the development and origin of oligodendrocytes in the rodent CNS, a population of immature cells that appeared to be precursors to oligodendrocytes was identified by the expression of the GD3 ganglioside.^[79]

In a separate series of studies, cells from

• List of human cell types derived from the germ layers

References