What Are the Roles of Oligodendrocyte Precursor Cells in Normal and Pathologic Conditions?

Adult oligodendrocyte precursor (or progenitor) cells (OPCs) are the most proliferative cells in the CNS and constitute approximately 10% of cells in the human brain.^1,2 Whereas their primary function is to generate mature myelinating oligodendrocytes,^2-4 there is increased evidence that OPCs have multiple myelination-independent functions in the nervous system both in health and disease.⁵ These cells constitute a heterogeneous population⁶ and have several unique properties (Figure).^4,7-10 As proposed in a recent review,⁵ OPCs may function as sensors of multiple environmental signals, integrate these signals to subsequently influence surrounding non-neural cells, and bidirectionally interact with axons to regulate circuit maturation and remodeling.⁵One salient feature of OPCs is that they receive direct synaptic input¹¹; express receptors for several neurotransmitters, including glutamate and γ-aminobutyric acid (GABA); and express a wide variety of ion channels.^12-14 This allows OPCs to precisely detect neuronal activity that regulates their development and differentiation, which is critical for activity-dependent (adaptive) myelination.^1,7-10 Reciprocally, OPCs may communicate with surrounding neurons and other cells by releasing several mediators through exocytosis¹⁵ or exosomes.¹⁶ OPCs have high metabolic demands,^17,18 which make them vulnerable to oxidative damage during hypoxia-ischemia.^19,20 They function as sensors of hypoxia and promote angiogenesis²¹ and respond to signals from astrocytes and microglia to contribute to neuroinflammation and glial scar formation.^22-24 Oligodendrocyte precursor cells have the potential for remyelination after injury but may have a limited role in human demyelinating disease.^25-27 Inability of proliferating OPCs to differentiate into mature oligodendrocytes leads to myelin loss in neurodegenerative disorders.²⁸ Oligodendrocyte precursors are the primary cell type for development of gliomas.²⁹ Thus, OPCs have a fundamental role both in the normal CNS and in a wide spectrum of pathologic conditions. There are recent reviews on the role of OPCs in health and disease,^5,30 and only some salient concepts will be emphasized in this paper.

Figure. Functions of Adult Oligodendrocyte Precursor Cells.

Adult oligodendrocyte precursor cells (OPCs) are functionally heterogeneous. They extend motile processes, proliferate, and migrate, and some of them differentiate into myelinating oligodendrocytes. They receive direct synaptic inputs from unmyelinated glutamatergic (Glu) axons and fast-spiking GABAergic interneurons and have a critical role in neuronal activity (adaptive) myelination. Synaptic signals elicit calcium (Ca²⁺) transients in OPC processes and cell bodies to control OPC development. These transients can by triggered by activation of Ca²⁺-permeable alpha-amino-3-hydroxy-5-methyl isoxazole propionic acid receptors (AMPARs), voltage-gated channels (such as L-type, Ca_v2.1 channels), GABA_A receptors (GABA_ARs), and purinergic P2X7 receptors activated by adenosine triphosphate (ATP). In OPCs, GABA_AR activation results in depolarization that can promote Ca²⁺ influx indirectly through voltage-gated sodium (Na⁺) channels (Na_v1.2, not shown) and the Na⁺/Ca²⁺ exchanger (NCX). Synaptic and other extracellular signals may promote OPC differentiation to oligodendrocytes for both activity-dependent myelination and remyelination after injury. OPCs may release GABA that inhibits fast-spiking inhibitory neurons; contact nodes of Ranvier, contributing to maintenance of extracellular of potassium (K⁺) homeostasis; participate in synaptic pruning and plasticity; and promote angiogenesis to support their high metabolic demands. OPCs cooperate and interact with astrocytes and microglia (not shown) in these processes and in mechanisms of neuroinflammation and gliosis. At the axon-myelin interface, N-methyl-D-aspartate receptors (NMDARs) mobilize glucose transporter 1 (GLUT-1), thereby promoting glucose intake by oligodendrocytes and production of lactate (and pyruvate), which is exported to axons through the monocarboxylic acid transporters (MCT)-1 and 2, thus providing an activity-dependent energy supply to axons.

Multiple Functions of Oligodendrocyte Precursor Cells

Development of Oligodendrocyte Precursor Cells

Oligodendrocyte precursor cells are progenitor cells that have the potential to differentiate into either myelinating oligodendrocytes or astrocytes according to environmental cues.³¹ They originate from the radial glia in the ventricular zone of the ventral forebrain brain and spinal cord and then expand and migrate to populate the gray and white matter of the entire CNS; they are subsequently replaced by OPCs born later in the dorsal cortex.^4,32 Oligodendrocyte precursor cells are characterized by the expression of neuron-glia antigen 2 (NG2), a chondroitin sulfate proteoglycan encoded by the CSPG4 gene,³³ and depend on platelet-derived growth factor (PDGF) secreted by neurons and astrocytes for their proliferation and migration.^4,34-36 Fetal OPCs have a bipolar morphology and migrate along the vasculature³⁷ and, when they encounter astrocytic end feet, detach from blood vessels,³⁸ move into the brain parenchyma, acquire a multiprocessed morphology, and may then either continue to differentiate into mature myelinating oligodendrocytes or remain as adult OPCs.³ Ventrally born OPCs also regulate migration of cortical GABAergic interneurons away from microvessels.³⁹ Adult OPCs self-renew and have a lifelong capacity to generate oligodendrocytes.^4,40,41 This process is tightly controlled by intrinsic and extracellular signals, including epigenetic mechanisms and transcription factors that participate in positive feedback loops (reviewed in References 42-46).

Features of Adult Oligodendrocyte Precursor Cells

Adult OPCs extend multiple processes that are highly dynamic, constantly survey their local environment, and locally interact with one another to maintain unique territories though self-repulsion.⁴⁷ The individual domains of adult OPCs overlap with those of astrocytes,^48,49 and within these domains, the 2 cell types form multiple contacts with each other, with the same neuron, and with pericytes, thus forming distinct functional units.⁴⁹ Oligodendrocyte precursors sense hypoxia through OPC-encoded hypoxia-inducible factor, which both stimulates their proliferation while arresting their maturation and stimulates angiogenesis through paracrine mechanisms.²¹

Neuron-Glia Synapses and Activity-Dependent Myelination

Neuronal activity regulates many aspects of OPC development and myelination.^7,50,51 Adult OPCs are the only glial cells that receive direct synaptic input,^11,12,52 express several types of voltage-gated and neurotransmitter-gated channels, sense level of extracellular potassium, and can generate local spikes and calcium (Ca²⁺) transients that affect their proliferation, migration, and differentiation.^53-60 Thus, OPCs have a critical role in activity-dependent (adaptive) myelination, which is critical for circuit development and refinement. Human studies show dynamic, circuit-specific increase in white matter fractional anisotropy (reflecting partly increase in myelination) in response training in a variety of tasks.^61,62 With aging, adult OPCs become both regionally and functionally heterogeneous and change their electrophysiologic activity and thus their differentiation potential.⁶³Glutamatergic and GABAergic axons make synapses at discrete sites along processes of OPCs in both the gray and white matter.^11,12,52 The transient activation of ionotropic glutamatergic and GABAergic receptors at these axoglial synapses elicits both global and localized Ca²⁺ transients that allow OPCs to precisely monitor ongoing neuronal activity and integrate synaptic inputs.^57,64 The synchronization of Ca²⁺ transients in neighboring OPCs allows the formation of local networks in which different OPC subsets may respond to neuronal activity with either proliferation or differentiation.⁶⁵ Unmyelinated glutamatergic axons innervate both their target neurons and neighboring OPCs^{11,12,58,66-68} and make synapses on OPCs within white matter tracts.^69-71 The pattern of glutamatergic activity differentially affects OPC proliferation and differentiation.^7,72 Vesicular release of glutamate from unmyelinated axon segments contacting OPC processes promotes myelin sheath formation.⁷³ Studies in vitro indicate that this effect is mediated primarily through Ca²⁺-permeable alpha-amino-3-hydroxy-5-methyl isoxazole propionic acid receptors (AMPARs).^12,64,74-77 These receptors also mediate use-dependent long-term potentiation at excitatory neuron-glia synapses^78,79 and may be important for remyelination in response to neuronal activity after injury.⁸⁰ By contrast, N-methyl-D-aspartate receptors (NMDARs) are present primarily in OPC processes, do not receive glutamatergic synapses, and have a role in myelin maintenance in oligodendrocytes.^81,82 Synaptic GABAergic inputs to OPCs primarily originate from fast-spiking interneurons that also target the proximal domains of neighboring neurons⁸³ Local GABAergic circuits affect OPCs through synaptic and extrasynaptic GABA_A and GABA_B receptors.^12,84,85 Activation of synaptic GABA_A receptors triggers small depolarization and increase in intracellular Ca²⁺ of OPCs^66,86-88 and may finely tune the capacity of self-maintenance of the OPCs.⁸⁹ GABA_B receptors may promote OPC differentiation and myelination.⁹⁰ Other signals, such as adenosine triphosphate (ATP), may also trigger intracellular Ca²⁺ transients in OPCs, either through influx through ion channels or release from intracellular stores.^57,91 For example, ATP may be released from vesicles in unmyelinated or premyelinated segments of axons in an activity-dependent manner or in response to injury⁹² and, both directly or through its byproduct adenosine, may act through different subtypes of purinergic receptors to affect different aspects of OPC development.⁹³ The level of intracellular Ca²⁺ affects proliferation of subsets of OPCs⁶⁵ and activates transcription factors necessary for oligodendrocyte differentiation.⁹⁴ Studies in vitro show that as oligodendrocytes develop and express maturation markers, they exhibit a progressive decrease in voltage-gated sodium and potassium channels and a loss of sodium-dependent spiking activity, concomitant with an increase in inwardly rectifying potassium channel activity and a switch in AMPAR composition.⁹⁵

Role of Oligodendrocyte Precursor Cells in Synaptic Plasticity

Adult OPCs also contribute to the organization and plasticity of neuronal circuits by mechanisms independent of myelinogenesis. In response to activity-dependent neural signals at axo-glia synapses, OPCs may release several mediators through exocytosis¹⁵ or exosomes,¹⁶ and these mediators may reciprocally affect surrounding neurons and synapses. For example, OPCs may release GABA,¹³ which elicits GABA_AR-mediated inhibition of local GABAergic interneurons, thus participating in organization of inhibitory microcircuits.^83,96 OPCs may also regulate long-term potentiation at glutamatergic synapses through activity-dependent cleavage of the NG2 proteoglycan⁹⁷ and secretion of several neuromodulatory factors.^97,98 Adult OPCs, like microglia and astrocytes, may also shape neuronal networks through pruning synapses and axonal branches and contribute to the refinement of neuronal circuits during cortical development.^99,100 These cells may also release several guidance molecules that can regulate axonal growth and synaptogenesis.^101,102 For example, studies in the visual system show that OPCs fine-tune neuronal circuits through axonal remodeling.¹⁰³ Similar to astrocytes, OPCs contact the nodes of Ranvier, where they may help maintaining extracellular K⁺ homeostasis.⁸³

Energy Demands of Adult Oligodendrocyte Precursor Cells

Adult OPCs are major consumers of glucose in the CNS¹⁸ and are characterized by a highly active pentose phosphate pathway.^17,18 They also produce acetyl coenzyme A that is metabolized in the tricarboxylic acid cycle.¹⁸ Compared with mature oligodendrocytes, adult OPCs consume approximately two-fold more oxygen¹⁰⁴ and contain more mitochondria to sustain oxidative phosphorylation and ATP production required for myelin formation.¹⁰⁵ This dependence on mitochondrial respiration decreases after myelination is complete.¹⁰⁵ To satisfy their high energy demand, adult OPCs directly promote angiogenesis in the setting of hypoxia by producing several proangiogenic factors to secure delivery of energy substrates.^21,106

Reciprocal Oligodendrocyte-Axon Interactions

Whereas the expression of synaptic receptors and ion channels becomes downregulated in mature myelinating oligodendrocytes,⁵⁴ axon-oligodendrocyte communication and localized Ca²⁺ activity continue to regulate different aspects of adaptive myelination.^8,107-109 Oligodendrocytes primarily use lactate both as a metabolic fuel and as a precursor for lipid synthesis and myelin formation.¹⁷ In mature oligodendrocytes, both NMDARs and GABA_BRs may be relevant in activity-dependent myelin growth and maintenance.^82,90 Mitochondrial release of Ca²⁺ at axonal and paranodal regions may also promote myelin remodeling independently of neuronal activity.¹¹⁰ In oligodendrocytes, stimulation of NMDARs mobilizes glucose transporter 1, leading to its incorporation into the myelin compartment; this allows activity-dependent glucose uptake and support of fast-spiking axons by releasing lactate and pyruvate, which are shuttled to the axon through monocarboxylic transporters.¹¹¹

Involvement of Adult Oligodendrocyte Precursor Cells in Neurologic Diseases

Adult OPCs may contribute to the pathogenesis of neurologic disorders by several mechanisms including cell degeneration and death, loss of function, and acquisition of an aberrant phenotype.³⁰

Hypoxia-Ischemia

The high oxygen demands and expression of Ca²⁺-permeable channels in OPCs predisposes them to cytoplasmic Ca²⁺ overload, oxidative stress, and excitotoxicity in the setting of hypoxia-ischemia.^19,20 Furthermore, Ca²⁺ overload at the axon-myelin interface leads to myelin sheath retraction and breakdown, for example, through activation of proteases such as calpain.^{19,81,112,113} Periventricular leukomalacia in premature neonates^114,115 and hypoxic-ischemic injury¹¹⁶ are typical examples of white matter injury due to excitotoxic OPC damage and death. Periventricular leukomalacia reflects selective vulnerability of perinatal late OPCs to oxidative stress.^117-119 In response to degeneration of OPCs, there is early and robust proliferation of neighboring OPCs, which fail to differentiate and initiate myelination despite the presence of intact-appearing axons.¹¹⁹ The persistence of these arrested populations of susceptible OPCs renders chronic white matter lesions vulnerable to recurrent hypoxia-ischemia.¹²⁰ The deep white matter is susceptible to injury in ischemic stroke.¹¹⁶ In addition to excitotoxic damage by glutamate and ATP,¹¹² hypoxia reduces GABAergic signaling through synaptic GABA_AR in OPCs, leading to their excessive proliferation and delayed differentiation.⁸⁷ One potential neuroprotective mechanism of hypothermia in the setting of ischemia is to prevents apoptosis of adult premyelinating OPCs.¹²¹

Multiple Sclerosis and Neuroinflammation

Oligodendrocyte precursor cells have a complex role in multiple sclerosis (MS) (reviewed in Reference 25). Adult OPCs seem to have only a limited role in myelin regeneration after demyelinating lesions in humans,^27,122 whereas surviving oligodendrocytes upregulate their expression of myelination-related genes and are able to regenerate new myelin sheaths.^27,123 The progressive oligodendrocyte depletion over the course of MS may reflect partly their defective proliferation and recruitment to the lesion.^25,124-127 Studies in pluripotential stem cell–derived oligodendroglia from patients with MS show that OPCs conserve their ability to interact with axons and generate myelin, indicating that failure of remyelination does not reflect an intrinsic defect of OPCs.¹²⁸ Some observations indicate that OPCs make new myelin more efficiently than preexisting oligodendrocytes.¹²⁹ In the setting of demyelination, OPCs respond to cytokines and chemokines released by microglia and other immune cells, which may promote OPC proliferation and differentiation into oligodendrocytes.^130,131 Oligodendrocyte precursors also have the potential to transdifferentiate into Schwann cells to assist remyelination.¹³² However, reactive OPCs can also actively participate in neuroinflammation both directly and through transformation into astrocytes, thereby contributing to impaired remyelination, reactive gliosis, and formation of the glial scar.^22,133-136 Reactive astrocytes secrete different combinations of cytokines, extracellular matrix proteins, and growth factors that influence survival, proliferation, and differentiation of adult OPCs.²⁴ Astrocytes derived from human-induced pluripotent stem cells of patients with MS can inhibit OPC differentiation and render OPCs able to adopt an immune profile.²³ Demyelination primes OPCs to express genes encoding molecules involved in immune responses,¹³⁷ including the receptor for interleukin (IL)–17, which inhibits OPC maturation and promotes inflammation.¹³⁸ Demyelination also induces OPCs to phagocytose and present myelin debris to cytotoxic T cells.¹³⁹ In active MS lesions, there is aberrant perivascular clustering of OPCs, which interferes with astrocyte end feet and endothelial tight junction integrity increasing permeability and disrupting the blood-brain barrier.¹⁴⁰ There is also a cross talk between adult OPCs and microglia. Whereas redistribution of iron from ferritin in the microglia to adult OPCs may contribute to myelin repair,¹⁴¹ accumulation of extracellular iron triggers release of proinflammatory cytokines from microglia, which is harmful for adult OPCs.¹⁴²

In response to injury, OPCs together with astrocytes and microglia proliferate and migrate to the lesion site and participate in the formation of the glial scar, where OPCs upregulate expression of several molecules that inhibit axonal growth, including the NG2 proteoglycan (chondroitin sulfate proteoglycan 4, CSPG4).¹⁴³ These cells may also entrap dystrophic axons within lesions through the formation of synaptic-like contacts, which may stabilize remodeling axons.^144,145

Neurodegeneration

With aging, adult OPCs decrease their proliferative activity,⁴⁷ become functionally heterogeneous both within and between brain regions,⁶³ and undergo many changes in their proteome, resulting in their reduced ability to differentiate into myelinating cells.^146-150 Similarly, disease-associated oligodendroglia show a unique transcriptome profile that is shared across neurodegenerative disorders.¹⁵¹ These include Alzheimer disease (AD),^152-155 amyotrophic lateral sclerosis (ALS),^156,157 and multiple system atrophy (MSA),¹⁵⁸ which show white matter pathology with proliferation of OPCs that are unable to differentiate into mature oligodendrocytes. In these disorders, cellular stress can affect the ability of OPCs to translate mRNAs into proteins required for myelination.²⁸ For example, in early AD, OPCs accumulate in the vicinity of β-amyloid plaques but are unable to differentiate, leading to myelin loss.^152-155 Impaired myelin formation may not directly result from Aβ accumulation¹⁵⁹ but is promoted by the expression of the apolipoprotein E4 allele resulting in disruption of cholesterol metabolism.¹⁶⁰ In ALS, impaired differentiation of OPCs into oligodendrocytes may reduce local energy supply to axons of motor neurons.^156,157 However, OPCs derived from induced pluripotent stem cells of patients with ALS carrying a pathogenic C9ORF72 variant did not exhibit impairment of maturation and maintained their viability despite the presence of RNA foci.⁹⁵ Multiple system atrophy is characterized by the accumulation of α-synuclein in the form of glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes.¹⁶¹ The role of OPCs in the formation of GCIs in adult oligodendrocytes remains to be fully understood.¹⁵⁸ In normal conditions, α-synuclein is expressed in OPCs but not in mature oligodendrocytes.¹⁶² Studies in experimental models show that abnormal α-synuclein impairs OPC differentiation into myelinating oligodendrocytes.¹⁶² However, whereas OPCs accumulate in MSA lesions, they do not show GCIs as do mature oligodendrocytes.¹⁶² Some studies suggest that GCI accumulation in oligodendrocytes may be due to their pruning of diseased axonal segments containing aggregated α-synuclein.¹⁶³ However, adult oligodendrocytes do not seem to incorporate fibrillary aggregates, whereas OPCs do, suggesting that they may promote formation of inclusions.¹⁶⁴

Glioma

Application of single-cell RNA sequencing in murine models of glioblastoma showed that OPCs disproportionately contribute to glioma formation.¹⁶⁵ Genes enriched in gliomas harboring isocitrate dehydrogenase (IDH) variants, including astrocytomas and oligodendrogliomas, are upregulated in OPCs and are key regulators of OPC specification and maintenance.²⁹ By contrast, genes involved in myelination are downregulated or absent in these tumors, indicating that all gliomas carrying IDH variants resemble early stages of OPC development with stalled oligodendrocyte differentiation.²⁹ The fact that OPCs respond to neural activity⁷ is relevant because there are glutamatergic synaptic inputs to glioma cells that drive both glioma progression^166,167 and migration of glioblastoma cells.¹⁶⁸

Perspective

Adult OPCs constitute a unique proliferating, functionally heterogeneous population of cells that have features critical for neuronal activity–dependent myelination and remyelination, synaptic plasticity, circuit remodeling, and neuroinflammation. They sense and integrate multiple signals from neurons, glia, and other surrounding cells and release mediators that reciprocally affect migrating neurons, axons, synpases, blood vessels, and immune responses. The involvement of adult OPCs in neurologic disorders reflects their susceptibility to oxidative stress and their ability to undergo reprograming during inflammation and neurodegeneration. Whereas enhancing OPC recruitment to demyelinating lesions may be a reasonable approach to accelerate remyelination,²⁵ the interactions among OPCs, neuroinflammation, and demyelination/remyelination are complex and probably depend on the disease state and environmental cues. The different effects of neuronal and non-neuronal signals on OPC proliferation, migration, and differentiation according to their developmental stage must be taken into consideration when designing pharmacologic tools to promote myelin formation and repair. Targeting specific transcriptional mechanisms using genetic approaches may also provide a potential therapeutic target for gliomas.

Glossary

AD

Alzheimer disease

ALS

amyotrophic lateral sclerosis

ATP

adenosine triphosphate

GCIs

glial cytoplasmic inclusions

IDH

isocitrate dehydrogenase

MS

multiple sclerosis

MSA

multiple system atrophy

NG2

neuron-glia antigen 2

NMDARs

N-methyl-D-aspartate receptors

OPCs

oligodendrocyte precursor cells

PDGF

platelet-derived growth factor

Appendix. Author

Name	Location	Contribution
Eduardo Benarroch, MD	Mayo Clinic, Rochester, MN	Drafting/revision of the article for content, including medical writing for content; major role in the acquisition of data

Study Funding

The author reports no targeted funding.

Disclosure

The author reports no relevant disclosures. Go to Neurology.org/N for full disclosures.