Polydendrocytes

Polydendrocytes (also known as NG2 cells, NG2 glia, or oligodendrocyte progenitor cells) are process-bearing glial cells (neuroglia) in the mammalian central nervous system (CNS) that are identified by the expression of the NG2 chondroitin sulfate proteoglycan (CSPG4) [1] and the alpha receptor for platelet-derived growth factor (PDGFRA).[2] They are distinct from other cell populations such as neurons, astrocytes, oligodendrocytes, microglia, and neural stem cells and are recognized as the fourth major glial cell type in the mammalian CNS. Studies have implicated polydendrocytes in many cellular and physiological processes. Polydendrocytes in the postnatal mouse CNS and those grown in culture generate oligodendrocytes, and thus they are often equated with oligodendrocyte progenitor cells (OPCs). Under some culture conditions, polydendrocytes give rise to astrocytes. A subpopulation of polydendrocytes in the gray matter of the embryonic CNS also generates protoplasmic astrocytes. In addition, polydendrocytes express receptors for various neurotransmitters and undergo membrane depolarization when they receive synaptic inputs from neurons.

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.[3][4]

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.[5] 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 (Pdgfra) 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.[6]

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,[7] and the antigen was named NG2 (nerve/glial antigen 2).[8][9] 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.[7][10] Comparison of NG2 and Pdgfra expression revealed that NG2 and Pdgfra are expressed on the same population of cells in the CNS.[11] These cells represent 2-9% of all the cells and remain proliferative in the mature CNS.[12]

Origin and fate

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 (sonic hedgehog). 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.[13] 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.[14] Using Cre-Lox recombination-mediated genetic fate mapping, several labs have reported the fate of polydendrocytes using different Cre driver and reporter mouse lines;[15][16][17][18] reviewed in reference.[19] 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.[20]

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.[21]

Functions

In remyelination

Polydendrocytes retain the ability to proliferate in adulthood and comprise 70-90% of the proliferating cell population in the mature CNS.[12][22] 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.[23][24] Similarly, polydendrocyte proliferation occurs in other types of injury that are accompanied by loss of myelin, such as spinal cord injury.[25]

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 (MS). 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.[25]

Numerous factors have been shown to regulate polydendrocyte proliferation, migration, and differentiation [25][25] (reviewed in [26][27][28]). In fresh MS lesions, clusters of HNK-1+ oligodendrocytes have been observed,[29] 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.[30] 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.[31] 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 [32] 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 [33] and white matter.[32][34] 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.[35][36]

Polydendrocytes can undergo cell division while maintaining synaptic inputs from neurons.[37] 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.

See also

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