By Isabella Savin
The canonical role of oligodendrocyte precursor cells (OPCs) in the brain is to mature into oligodendrocytes (OLs), the cells that produce the fatty myelin sheath enwrapping neurons. Upon recognition of damaged myelin, OPCs migrate to the site of damage and undergo a strict differentiation programme into OLs. OPCs persist throughout all 6 cortical layers and comprise approximately 5% of the cells in the adult brain, and are an attractive therapeutic target for neurodegenerative diseases; for instance, stimulating RXR-γ signalling in peripheral OPCs accelerates remyelination in mouse models of multiple sclerosis (MS).1 A rapidly growing body of evidence suggests that these cells have a wide variety of roles within the nervous system, including in some of the most complex processes of the brain, such as memory formation.
Unexpectedly, OPCs have proven to have a broad capacity for differentiation, and are far from mere OL precursors. OPCs express several distinct markers, particularly platelet-derived growth factor receptor alpha (PDGFRα) and neural/glial antigen 2 (NG2), enabling their fate in vivo to be easily mapped. OPCs seemingly have a strong differentiation bias towards astrocytes (second only to OLs), abundant glial cells which regulate blood flow to the brain and provide support for neurons. Remarkably, knocking out only one transcription factor in OPCs, Olig2, is sufficient to cause astrocyte differentiation.2 Intriguingly, OPCs can generate OLs with different properties, depending on where they are derived. OPCs originate deep within the brain in the ventricular zone (VZ), and OPCs from the dorsal VZ usually mature into OLs with more active roles in myelination compared to ventrally-derived OLs, and preferentially myelinate more dorsal tracts.3
Controversially, there are even suggestions that OPCs can differentiate into neuronal cells. Robins et al. found cells expressing neural markers derived from NG2+ cells in the piriform cortex and hypothalamus of transgenic mice4, and a recent single-nucleus RNA-sequencing (snRNA-seq) dataset showed that some human OPCs express neurogenesis and neural differentiation markers.5 Whether OPC-derived neurons are found in significant numbers in vivo – indeed, only around 1% of the neurons identified by Robins et al. were derived from OPCs4 – or whether they make any functional contribution to neural circuits is yet to be determined.
While the ability of OPCs to give rise to neurons remains hotly disputed, the fact they form functional synapses with neural cells is more well-established. For instance, electrophysiological studies have revealed that OPCs form excitatory connections with neural cells in the trisynaptic circuit of the hippocampus.6 Moreover, these OPC-neuron connections undergo a process called long-term potentiation (LTP), wherein their electrical excitability increases due to increased neuronal firing over time – a process traditionally considered to occur exclusively at neuron-neuron synapses.6 The formation of OPC-neuron synapses within the hippocampus, a critical brain structure for memory formation and consolidation, along with the evidence for LTP, considered a crucial molecular mechanism for learning, raises tantalising questions about the role of OPCs in higher cognitive processes. It must be noted that these electrophysiological recordings were performed in mouse cortical slices and whether OPCs establish similar connections in humans is presently unknown. However, it is generally accepted that OPCs play a role in memory across species through their ability to differentiate into myelin-producing cells.7 Indeed, Pan et al. generated “conditional knockout” mice in which the Myrf transcription factor was deleted exclusively in OPCs, inhibiting myelin biogenesis and resulting in long-term memory deficits.8 OPCs also contribute to remodelling of existing myelin tracts in response to external stimuli, improving connectivity between brain regions – critical processes in memory formation.7
In addition to forming close contacts with neurons, OPCs are intimately associated with the brain vasculature, and are required for proper maintenance of the blood-brain barrier (BBB) through signalling to endothelial cells (ECs).9 This ensures the brain is supplied with sufficient nutrients and that toxic substances in the blood do not reach neural tissue. However, OPCs are frequently dysfunctional in neurodegenerative disorders, contributing to compromised BBB integrity. For instance, OPCs in lesions from MS patients form large aggregations around vessels, displacing associated astrocytes and weakening tight junctions between ECs9, causing leakage of immune cells and inflammation of surrounding tissue. This effect of clustered OPCs on ECs was attributed to hyperactivated Wnt signalling, later validated by a 2020 study in which functional OPCs were transplanted into brains of ischaemic mice, restoring normal Wnt signalling to ECs and even reforming the tight junctions between them.10 The mechanism of OPC clustering around vessels, however, is still unclear – in future, identifying and potentially inhibiting pathways behind OPC aggregation could attenuate BBB damage in neurodegenerative diseases.
Finally, OPCs are also emerging as critical players in synaptic pruning, a process occurring in the maturing brain which eliminates under-stimulated synapses. The highly branched morphology of OPCs and the difficulty of isolating and purifying them has previously presented barriers to investigating this role of OPCs. However, a recent study by Buchanan et al.12 employed transmission electron microscopy with 3D reconstruction to elucidate OPCs’ role in pruning of the mouse visual cortex. The authors identified phagolysosomes (PLs) – small vesicles involved in digesting foreign or intracellular material – in some OPCs, which contained fragments of neurons. This was subsequently validated by snRNA-seq, which showed these OPCs were significantly enriched for genes involved in phagocytosis. Surprisingly, PL density was greater in OPCs than in microglia, usually considered the key cells mediating synaptic pruning. However, since the OPCs were isolated from static slices – and then again, only from layers 2 and 3 – the mechanisms underlying pruning by OPCs remain a matter of speculation, as is whether OPCs eliminate synapses in other regions.
While OPCs’ main role is to mature into oligodendrocytes, these cells are evidently more multifaceted than originally thought. Some roles of OPCs identified in these studies have uprooted long-standing dogmas of neurobiology – the idea that memory formation could involve synapses other than those between two neurons was unthinkable a few decades ago. However, there remains significant work to be done to clarify the mechanisms behind OPCs’ involvement in learning, neurodegeneration, and cortical development.
- Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience. 2011;14(1):45–53.
- Zhu X, Zuo H, Maher BJ, Serwanski DR, LoTurco JJ, Lu QR, et al. Olig2-dependent developmental fate switch of NG2 cells. Development. 2012 May 23;139(13):2299–307.
- Nishiyama A, Shimizu T, Sherafat A, Richardson WD. Life-long oligodendrocyte development and plasticity. Seminars in Cell & Developmental Biology. 2021;116:25–37.
- Robins SC, Trudel E, Rotondi O, Liu X, Djogo T, Kryzskaya D, et al. Evidence for NG2-glia Derived, Adult-Born Functional Neurons in the Hypothalamus. PLoS ONE. 2013;8(10):e78236.
- Chamling X, Kallman A, Fang W, Berlinicke CA, Mertz JL, Devkota P, et al. Single-cell transcriptomic reveals molecular diversity and developmental heterogeneity of human stem cell-derived oligodendrocyte lineage cells. Nature Communications. 2021;12(1):652.
- Ge WP, Yang XJ, Zhang Z, Wang HK, Shen W, Deng QD, et al. Long-Term Potentiation of Neuron-Glia Synapses Mediated by Ca2+-Permeable AMPA Receptors. Science. 2006;312(5779):1533–7.
- Munyeshyaka M, Fields RD. Oligodendroglia are emerging players in several forms of learning and memory. Communications Biology. 2022;5(1).
- Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation. Nature Neuroscience. 2020;23(4):487–99.
- Kimura I, Dohgu S, Takata F, Matsumoto J, Watanabe T, Iwao T, et al. Oligodendrocytes upregulate blood-brain barrier function through mechanisms other than the PDGF-BB/PDGFRα pathway in the barrier-tightening effect of oligodendrocyte progenitor cells. Neuroscience Letters. 2020;715:134594.
- Niu J, Tsai HH, Hoi KK, Huang N, Yu G, Kim K, et al. Aberrant oligodendroglial–vascular interactions disrupt the blood–brain barrier, triggering CNS inflammation. Nature Neuroscience. 2019;22(5):709–18.
- Wang L, Geng J, Qu M, Yuan F, Wang Y, Pan J, et al. Oligodendrocyte precursor cells transplantation protects blood–brain barrier in a mouse model of brain ischemia via Wnt/β-catenin signaling. Cell Death & Disease. 2020;11(9).
- Buchanan J, Elabbady L, Collman F, Jorstad NL, Bakken TE, Ott C, et al. Oligodendrocyte precursor cells ingest axons in the mouse neocortex. PNAS. 2022;119(48).