Oligodendrocyte progenitor cell


Oligodendrocyte progenitor cells, also known as oligodendrocyte precursor cells, NG2-glia or polydendrocytes, are a subtype of glial cells in the central nervous system. They are process-bearing glial cells in the mammalian central nervous system that are identified by the expression of the NG2 chondroitin sulfate proteoglycan and the alpha receptor for platelet-derived growth factor. 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. A subpopulation of polydendrocytes in the gray matter of the embryonic CNS also generates protoplasmic astrocytes.
The loss or lack of OPCs, and consequent lack of differentiated oligodendrocytes, is associated with a loss of myelination and subsequent impairment of neurological functions. In addition, polydendrocytes express receptors for various neurotransmitters and undergo membrane depolarization when they receive synaptic inputs from neurons.

Structure

Oligodendrocyte progenitor cells are a subtype of glial cells in the central nervous system, characterized by expression of the proteoglycans PDGFRA, and CSPG4. OPCs are smaller than neurons, of comparable size to other glia, and can either have a bipolar or complex multipolar morphology with processes reaching up to ~50 μm.
OPCs encompass approximately 3-4% of cells in the grey matter and 8-9% in white matter, making them the fourth largest group of glia after astrocytes, microglia and oligodendrocytes.
OPCs are particularly prevalent in the hippocampus and in all layers of the neocortex. In white matter, OPCs are found along unmyelinated axons as well as along myelinated axons, engulfing nodes of Ranvier. Recently, OPCs have been shown to reside in close contact with NG2-expressing pericytes in cerebral white matter, as well.
OPCs have a remarkable homogenic distribution throughout the brain. This is achieved through active self-repulsion, causing the cells to be generally equally spaced from one another. OPCs constantly survey their surroundings through actively extending and retracting processes that have been termed growth cone like processes. Death or differentiation of an OPC is rapidly followed by migration or local proliferation of a neighbouring cell.
OPCs receive synaptic contacts onto their processes from both glutamatergic and GABAergic neurons. OPCs receive preferred somatic contacts from fast-spiking GABAergic neurons, while non-fast spiking interneurons have a preference for contacting the processes. These inhibitory connections occur mainly during a specific period in development, from postnatal day 8 till postnatal day 13.

Development

OPCs originate in the neuroepithelium of the spine and migrate to other areas of the brain. Several waves of OPC production and migration lead to the generation of oligodendrocytes. OPCs are highly proliferative, migratory and bipolar. The first wave of OPC production originates in the ganglionic eminence.
As development progresses a second and third wave of OPCs originate from the lateral and caudal ganglionic eminences and generate the majority of adult oligodendrocytes. OPCs then migrate across most of the developing brain and spinal cord and eventually myelinate the entire central nervous system. They differentiate into the less mobile, pro-oligodendrocytes that further differentiate into oligodendrocytes, a process characterized by the emergence of the expression of myelin basic protein, proteolipid protein, or myelin-associated glycoprotein. 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. The various waves of OPCs could myelinate distinct regions of the brain, which suggests that distinct functional subpopulations of OPCs perform different functions.
OPCs are found in both white and gray matter. However, the number of OPCs is higher in white matter than in gray matter because of a higher rate of proliferation in the former. White matter OPCs proliferate and contribute to adult oligodendrogenesis, while gray matter OPCs are slowly proliferative or quiescent and mostly remain in an immature state. White and gray matter OPCs have different resting membrane potentials and ion channel expression. Gray matter lacks voltage-gated sodium channels while white matter does not and produces action potentials. Cells that produce action potentials can receive signals from other neurons. These differences in OPC function depend on their locations.
Through maturation, OPCs are produced in the sub-ventricular zone. The stem cells in the SVZ generate C cells which produce OPCs that go into the olfactory bulb. The number of oligodendrocytes that are later formed depends on the part of the SVZ they came from. More oligodendrocytes are produced from the dorsal part of the SVZ than the ventrolateral part, and more are produced from the posterior than the rostral part. This is due to differing environmental factors in these locations. The Wnt in the dorsal part favors OPC specification and the Bmp in the ventral part inhibits it. These molecules help cause the expression of certain transcription factors.
Expression of Olig2 generates motor neurons and OPCs, dependent on the Shh and regulated by the Notch signaling pathway. This regulation limits the number of motor neurons and allows more oligodendrocytes to be produced. Olig2 is one of the most important transcription factors involved in oligodendrocyte production. Olig2 inactivation during development reduces OPC production.
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. Laminin, a component of the extracellular matrix, plays an important role regulating oligodendrocyte production. Mice lacking laminin alpha2-subunit produced fewer OPCs in the SVZ. MicroRNA plays a role in the regulation of oligodendrocyte differentiation and myelin maintenance. Deletion of Dicer1 in miRNA disrupts normal brain myelination. However, miR-7a, and miRNA in OPCs, promotes OPC production during brain development.
Multiple pathways cause oligodendrocyte branching, but their specific contributions have yet to be resolved and the process by which oligodendrocytes extend and wrap around multiple axons remains poorly understood.

Origin

In the embryonic spinal cord, a major source of polydendrocytes is the ventral ventricular zone of the pMN domain marked by the expression of the transcription factors Olig1 and Olig2 and the p3 domain that expresses Nkx2.2, which are induced by the morphogen Shh. Some polydendrocytes also arise from the dorsal ventricular zone. In the forebrain, three regionally distinct sources have been shown to generate polydendrocytes sequentially: an early ventral source from the medial ganglionic eminence marked by Nkx2.1, followed by progenitor cells in the lateral ganglionic eminence marked by Gsh2, and finally the dorsal neocortical germinal zone marked by Emx1. After the committed progenitor cells exit the germinal zones, they begin to express NG2 and Pdgfra and expand by local proliferation and migration and eventually occupy the entire CNS parenchyma. Polydendrocytes continue to exist in the adult CNS and retain their proliferative ability throughout life.

Fate

The fate of polydendrocytes has been highly debated. Using Cre-Lox recombination-mediated genetic fate mapping, several labs have reported the fate of polydendrocytes using different Cre driver and reporter mouse lines; reviewed in reference. The consensus of these studies is that polydendrocytes generate predominantly oligodendrocytes in both gray and white matter. The rate at which they generate oligodendrocytes declines with age and is greater in white matter than in gray matter. These studies revealed that up to 30% of the oligodendrocytes that exist in the adult corpus callosum are generated de novo from polydendrocytes over a period of 2 months. It is not known whether all polydendrocytes eventually generate oligodendrocytes while self-renewing its population or whether some remain as polydendrocytes throughout the life of the animal and never differentiate into oligodendrocytes.
Using NG2cre mice, it was shown that polydendrocytes in the prenatal and perinatal gray matter of the ventral forebrain and spinal cord generate protoplasmic astrocytes in addition to oligodendrocytes. However, contrary to the prediction from optic nerve cultures, polydendrocytes in white matter do not generate astrocytes. When the oligodendrocyte transcription factor Olig2 is deleted specifically in polydendrocytes, there is a region- and age-dependent switch in the fate of polydendrocytes from oligodendrocytes to astrocytes.
Although controversy still continues about the neuronal fate of polydendrocytes, the consensus from a number of recent genetic fate mapping studies described above seems to be that polydendrocytes do not generate a significant number of neurons under normal conditions, and that they are distinct from neural stem cells that reside in the subventricular zone.

Function

OPCs were long held to function purely as progenitors to oligodendrocytes, hence the name. Later, additional functions were suggested.
The primary function is to serve as precursor for oligodendrocytes as well as some protoplasmic astrocytes in grey matter. Postnatally, OPCs remain lineage-restricted and generally only differentiate into oligodendrocytes.
Whereas some studies suggested that OPCs can generate cortical neurons, other studies rejected these findings. The question is unresolved, as studies continue to find that certain populations of OPCs can form neurons.
OPCs synthesize the neuromodulatory factors prostaglandin D2 synthase and neuronal pentraxin 2. This is mediated by the protein NG2, whose intracellular domain can be cleaved by the γ-secretase and translocated to the nucleus.
The two N-terminal LNS domains of the NG2 ectodomain can modulate signalling via AMPA and NMDA receptors of neuronal synapses within the cortex, including neuronal LTP. The NG2 ectodomain is released into the ECM from the full-length NG2 protein by constitutive and activity-dependent activity of the ADAM10 protease, showing that NG2 can modulate the neuronal glutamatergic system.
Recent work has also illustrated that OPCs can act as antigen presenting cells. They have been shown to express functional MHC II and initiate a learnt CD4+ immunological response.

Remyelination

Spontaneous myelin repair was first observed in cat models. It was later discovered to occur in the human CNS as well, specifically in cases of multiple sclerosis. Spontaneous myelin repair does not result in morphologically normal oligodendrocytes and is associated with thinner myelin compared to axonal diameter than normal myelin. Despite morphological abnormalities, however, remyelination does restore normal conduction. 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%. Comparative studies of cortical lesions reported a greater proportion of remyelination in the cortex as opposed to white matter lesions.
Polydendrocytes retain the ability to proliferate in adulthood and comprise 70-90% of the proliferating cell population in the mature CNS. Under conditions in the developing and mature CNS where a reduction in the normal number of oligodendrocytes or myelin occurs, polydendrocytes react promptly by undergoing increased proliferation. In acute or chronic demyelinated lesions created in the rodent CNS by chemical agents such as lysolecithin or cuprizone, polydendrocytes proliferate in response to demyelination, and the proliferated cells differentiate into remyelinating oligodendrocytes. Similarly, polydendrocyte proliferation occurs in other types of injury that are accompanied by loss of myelin, such as spinal cord injury.
If polydendrocytes were capable of giving rise to myelinating oligodendrocytes, one would expect complete remyelination of pathologically demyelinated lesions such as those seen in multiple sclerosis. However, complete myelin regeneration is usually not observed clinically or in chronic experimental models. Possible explanations for remyelination failure include depletion of polydendrocytes over time, failure to recruit polydendrocytes to the demyelinated lesion, and failure of recruited polydendrocytes to differentiate into mature oligodendrocytes.
Numerous factors have been shown to regulate polydendrocyte proliferation, migration, and differentiation . In fresh MS lesions, clusters of HNK-1+ oligodendrocytes have been observed, which suggests that under favorable conditions polydendrocytes 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. The mechanisms that regulate differentiation of polydendrocytes into myelinating oligodendrocytes are an actively investigated area of research.
Another unanswered question is whether the polydendrocyte pool eventually becomes depleted after they are used to generate remyelinating cells. Clonal analysis of isolated polydendrocytes in the normal mouse forebrain suggests that in the adult, most clones originating from single polydendrocytes consist of either a heterogeneous population containing both oligodendrocytes and polydendrocytes or consist exclusively of polydendrocytes, suggesting that polydendrocytes in the adult CNS are able to self-renew and are not depleted under normal conditions. However, it is not known whether this dynamic is altered in response to demyelinating lesions.

Neuron-polydendrocyte interactions

There is substantial evidence that indicates a functional interaction between polydendrocytes and neurons.

Node of Ranvier

Polydendrocytes extend their processes to the nodes of Ranvier 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 polydendrocytes to sense and possibly respond to neuronal activity

Neuron-polydendrocyte synapse

Studies have shown that neurons form synapses with polydendrocytes in both gray matter and white matter. Polydendrocytes express the AMPA type glutamate receptors and GABAA receptors and undergo small membrane depolarizations when stimulated by glutamate or GABA that is vesicularly released from presynaptic terminals. Electron microscopy revealed polydendrocyte membranes apposed to neuronal presynaptic terminals filled with synaptic vesicles. Polydendrocytes lose their ability to respond to synaptic inputs from neurons as they differentiate into mature oligodendrocytes.
Polydendrocytes can undergo cell division while maintaining synaptic inputs from neurons. 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 polydendrocytes can receive synaptic inputs and generate myelinating oligodendrocytes. The functional significance of the neuron-polydendrocyte synapses remains to be elucidated.

Cell types

Mature oligodendrocytes are unlikely to contribute to spontaneous remyelination even if they survive the original demyelinating injury. New oligodendrocytes have been observed in areas of myelin damage, although the source of these new cells is unresolved. One possibility is that mature oligodendrocytes from uninjured areas migrate to the injury site and engage in myelination. This is unlikely because the transplantation of mature human oligodendrocytes achieve minimal myelin formation in the demyelinated rodent CNS. Another possibility is that mature oligodendrocytes de-differentiate into OPCs that then proliferate and remyelinate, Little experimental evidence supports this view.

Transplantation

OPC transplants contribute to remyelination, but it is difficult to maintain such cells in adequate concentrations at high purity. 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. Adult central nervous system stem cells have also been shown to generate myelinating oligodendrocytes, but are not readily accessible.
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. 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.

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.
In a separate series of studies, cells from perinatal rat optic nerves that expressed the A2B5 ganglioside were shown to differentiate into oligodendrocytes in culture. Subsequently, A2B5+ cells from other CNS regions and from adult CNS were also shown to generate oligodendrocytes. Based on the observation that these cells require PDGF for their proliferation and expansion, the expression of the alpha receptor for platelet-derived growth factor was used to search for the in vivo correlates of the A2B5+ cells, which led to the discovery of a unique population of Pdgfra+ cells in the CNS whose appearance and distribution were consistent with those of developing oligodendrocytes.
Independently, Stallcup and colleagues generated an antiserum that recognized a group of rat brain tumor cell lines, which exhibited properties that were intermediate between those of typical neurons and glial cells. Biochemical studies showed that the antiserum recognized a chondroitin sulfate proteoglycan with a core glycoprotein of 300 kDa, and the antigen was named NG2. NG2 was found to be expressed on A2B5+ oligodendrocyte precursor cells isolated from the perinatal rat CNS tissues and on process-bearing cells in the CNS in vivo. Comparison of NG2 and Pdgfra expression revealed that NG2 and Pdgfra are expressed on the same population of cells in the CNS. These cells represent 2-9% of all the cells and remain proliferative in the mature CNS.