Rethinking the Oligodendrocyte Progenitor Cell: One Cell, Many Functions

ABSTRACT

Oligodendrocyte progenitor cells (OPCs) are resident progenitors and the largest cycling nonneuronal population of the central nervous system (CNS). For decades, OPCs were defined by a single output—the myelinating oligodendrocyte. However, a growing body of evidence has since revealed a cell whose functions reach well beyond myelin, raising the question of whether the OPC should be regarded as a glial cell type in its own right. In this review I examine a broader repertoire of OPC functions and their relevance to CNS health and disease, alongside myelination, remyelination and myelin maintenance. Beyond forming myelinating oligodendrocytes, OPCs tune myelination to neuronal activity, regulate neural circuits directly, influence the vasculature and blood–brain barrier and act as immune sensors and effectors. These emerging myelin‐independent functions establish OPCs as active participants in CNS physiology and pathology rather than a cell defined solely by the oligodendrocytes it produces. Finally, I consider two challenges shared across all these functions and that have, until now, been studied almost exclusively in relation to myelination: OPC heterogeneity and ageing. Whether these noncanonical functions are performed by all OPCs or by distinct subsets and inducible states and how each function is shaped across the lifespan and in pathological contexts, remains unresolved. I propose that addressing these questions is essential to understanding the relevance of these different OPC functions in health and disease.

Oligodendrocyte progenitor cells (OPCs) are increasingly recognised as multifunctional CNS cells rather than mere precursors of myelinating oligodendrocytes. Alongside myelination and remyelination, they contribute to myelin and circuit plasticity, circuit regulation, vascular and blood–brain barrier regulation and neuroimmune modulation. Both OPC heterogeneity and ageing shape how these functions operate in health and disease.

Abbreviations

AMPA

α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid

B2m

beta‐2‐microglobulin

BBB

blood–brain‐barrier

C4b

complement 4 b

CCL2

C‐C motif chemokine ligand 2

CNS

central nervous system

CXCR4

C‐X‐C motif chemokine receptor 4

DA‐OPC

disease‐associated OPC

E

embryonic

EAE

experimental autoimmune encephalomyelitis

GABA

gamma aminobutiric acid

HIF

hypoxia inducible factor

IFNγ

interferon gamma

IL1β

interleukin 1 beta

LPS

lipopolysaccharide

LRP1

low density lipoprotein receptor related protein

MHCI

major histocompatibility complex I

MHCII

major histocompatibility complex II

MMP9

matrix metalloprotease 9

MS

multiple sclerosis

NG2

nerve/glial antigen 2

NMDA

N‐methyl‐D‐aspartate

OLIG2

oligodendrocyte transcription factor 2

OPC

oligodendrocyte progenitor cell

PD‐L1

programmed death ligand 1

PD‐L2

programmed death ligand 2

PDGFRα

platelet‐derived growth factor α

PolyI:C

polyinosinic:polycytidylic acid

RNA

ribonucleic acid

SASP

senescent‐associated secretory phenotype

SOX10

SRY box transcription factor 10

TGFβ1

transforming growth factor beta 1

TNFα

tumour necrosis factor alpha

Wnt

Wnt/β catenin signalling pathway

1. Introduction

Oligodendrocyte progenitor cells (OPCs) are tissue‐resident progenitors in the central nervous system (CNS) and the largest cycling nonneuronal population, accounting for approximately up to 5% of all CNS cells (Dawson 2003; Psachoulia et al. 2009). As progenitors, they self‐renew and give rise principally to myelinating oligodendrocytes during development and adulthood though they can also generate astrocytes and, under certain injury conditions, Schwann cells (Crawford et al. 2014; Kang et al. 2010; Tripathi et al. 2010; Zawadzka et al. 2010; Zhao et al. 2009; Zhu et al. 2008). Unlike most tissue‐resident progenitors, OPCs do not occupy discrete niches: they are highly dynamic cells distributed throughout the CNS, tiling the parenchyma in nonoverlapping territories and persisting across the entire lifespan (Dawson 2003; Heo et al. 2025; Hughes et al. 2013; Psachoulia et al. 2009; Rivers et al. 2008). The abundance of OPCs throughout life and their morphological and transcriptional differences with oligodendrocytes together with the emergent myelin‐independent functions attributed to OPCs suggest that OPCs are probably more than just a progenitor cell and raise the question of whether OPCs should be regarded as a separate glial cell type (Akay et al. 2021; Xiao and Czopka 2023).

The evidence for the conventional progenitor view is, of course, substantial (Figure 1). OPCs generate oligodendrocytes postnatally as the CNS matures, but also throughout life, contributing to myelin turnover (Hill et al. 2018; Hughes et al. 2013; Thornton et al. 2024). OPCs are also responsible for the regenerative response to injury, in which OPCs proliferate, migrate to sites of damage and form new oligodendrocytes that restore myelin around bare axons and prevent their degeneration (Franklin and Ffrench‐Constant 2017; Gensert and Goldman 1997). This remyelinating capacity is essential to axonal health in primary demyelinating disorders such as multiple sclerosis (MS) (Franklin et al. 2012) and in other conditions increasingly recognised to involve myelin pathology, including Alzheimer's and Parkinson's disease (Bae et al. 2023; Behrendt et al. 2013; Desai et al. 2010; Wu et al. 2017). The view of remyelination as an active response of OPCs to myelin demand or damage is now also debated. Recent work suggested that OPCs differentiate continuously throughout the adult CNS as the result of a constitutive differentiation programme instead of in response to myelin demand, but this continuous differentiation is only captured as regenerative when newly formed oligodendrocytes are retained to meet a myelination need (Mironova et al. 2026). This debate in itself highlights the complexity of OPC biology.

FIGURE 1.

Myelin‐dependent OPC functions. OPCs have been traditionally studied as progenitors that give rise to myelinating oligodendrocytes during developmental myelination and during myelin turnover in adulthood. OPCs are also responsible for remyelination and upon myelin damage OPCs activate, proliferate and migrate to the lesion area, where they differentiate into myelin forming oligodendrocytes and restore lost myelin. Additionally, OPCs also respond to neuronal activity differentiating into new myelinating oligodendrocytes that change myelin in response to neuronal activity by adding myelin to previously unmyelinated axons or changing myelin thickness or length.

The same properties that make OPCs effective myelinating progenitors also place them at the centre of several functions beyond myelin formation. OPCs sense neuronal activity to tune myelination to experience, contributing to myelin and circuit plasticity; they shape neural circuits directly through synaptic contacts and the remodelling of axons and synapses independently of myelin; they regulate the vasculature, building, maintaining and at times disrupting the blood–brain barrier (BBB) and they operate as immune sensors and effectors that modulate neuroinflammation (Akay et al. 2021; Fernandez‐Castaneda and Gaultier 2016; Xiao and Czopka 2023) (Figure 2). These functions are nonetheless newly described, mechanistically unresolved and their alterations in disease are only beginning to be understood. This review examines these emerging OPC functions, before considering how they may be influenced by heterogeneity and ageing.

FIGURE 2.

Myelin‐independent OPC functions. Emerging evidence has shown that OPCs have novel functions that do not depend on their capacity to form new myelinating oligodendrocytes. OPCs form synapses with neurons enabling a direct regulation of neural circuits either by the engulfment of synapses or direct regulation of neuronal arborization. OPCs are key regulators of vascularization and BBB maintenance, properties that are altered with changes in OPC number or inflammation, contributing to alterations in CNS vascularization and BBB damage. OPCs also act as immune sensors and effectors, expressing a wide range of cytokines and chemokines, immune regulatory pathways (e.g., PDL1) and antigen processing and presentation machinery that enable OPCs to either suppress or activate innate and adaptive immune cell–mediated inflammation in a context dependent manner.

2. Origin Identity and Heterogeneity

OPCs were first identified in the early 1980s by Raff and colleagues (Ffrench‐Constant and Raff 1986a, 1986b; Raff et al. 1983). During embryonic development OPCs arise in successive waves from distinct regions of the brain and spinal cord. In vivo fate‐mapping studies combined with different knockout strategies have shown that, in the spinal cord, 85% of OPCs are generated from the ventral zone of the neuroepithelium around embryonic day 12.5 (E12.5), followed by a more dorsal wave occurring around E16.5 that occupies the dorsal horn and lateral funiculi. In the brain, a comparable sequence unfolds: a first ventral wave emerges from the medial ganglionic eminence and a second arises from the lateral and caudal ganglionic eminence around E15 populating the entire cortex with OPCs from ventral origin. After birth, a third wave originates from the dorsal neuroepithelium in the cortex itself. The earlier ventrally derived populations progressively diminish in the postnatal forebrain as this dorsal wave expands. The OPCs that persist in the adult brain therefore derive from both dorsal and ventral forebears and can be identified by the expression of lineage‐defining transcription factors (OLIG2 and SOX10) together with defined surface markers such as platelet‐derived growth factor receptor alpha (PDGFR α), nerve‐glial antigen 2 (NG2) or A2B5 (Kessaris et al. 2005; Richardson et al. 2006; Tripathi et al. 2011).

Although adult OPCs from these different origins converge to a largely common molecular profile, their developmental origin is not functionally neutral. In vivo fate‐mapping studies coupled with diphtheria toxin‐mediated depletion of OPCs originating from different waves have shown that the loss of dorsal oligodendrocytes can be compensated by ventral OPCs. However, this compensation is imperfect producing subtle changes in forebrain myelination alongside motor and cognitive alterations (Foerster et al. 2024). Developmental origin also shapes OPC regenerative behaviour, with dorsally derived OPCs reported to display enhanced proliferation, migration and differentiation, yet also greater susceptibility to age‐associated functional decline (Crawford et al. 2016).

Beyond developmental origin, OPCs are subject to further sources of heterogeneity. They exhibit marked regional diversity. For example, grey and white matter OPCs differ in their transcriptome and electrophysiological properties, which translates into distinct proliferative and differentiation capacities (Dimou et al. 2008; Dimou and Simons 2017; Larson et al. 2016; Marques et al. 2016; Viganò et al. 2013). Heterogeneity is also apparent between brain‐ and spinal cord–derived OPCs which show distinct differentiation and myelination potential (Bechler et al. 2015). This heterogeneity has also been investigated at transcriptomic level with bulk and single cell RNA sequencing approaches. While myelinating oligodendrocytes display considerable transcriptional heterogeneity, OPCs appear comparatively homogenous in the healthy adult CNS, subdividing mainly according to their quiescent, cycling or differentiating state, although the extent of this homogeneity remains debated (Heo et al. 2025; Marques et al. 2016, 2018; Spitzer et al. 2019). Notably, in vivo time‐lapse of OPCs in the zebrafish has shown that OPC subsets with distinct functions (e.g., regulating either local OPC number or differentiation into myelinating oligodendrocytes) are distinguished by the position of their soma, arguing that at least part of this diversity is acquired from the local environment rather than intrinsically specified (Marisca et al. 2020). Despite this growing evidence for OPC heterogeneity at multiple levels, we still do not know how well it maps onto the human CNS, and we lack robust markers that would allow the different OPC subsets to be functionally lineage‐traced. This remains a central barrier to understanding the relevance of distinct OPC subsets and states in CNS health and disease.

3. Myelin Plasticity and Neuronal Circuit Regulation

Although myelin formed during development has been long considered static, it is now well recognised as a dynamic substrate of CNS plasticity and consequentially, OPCs are increasingly understood not merely as the source of that plastic myelin but as circuit elements in their own right, acting on neurons both in a myelin‐dependent and independent manner.

The myelin‐dependent circuit regulatory function of OPCs, also known as myelin plasticity, is the better‐established of the two and has been extensively reviewed in the field (Bujalka and Emery 2017; Kaller et al. 2017; Mount and Monje 2017; Osso and Hughes 2024; Purger et al. 2016; Williamson and Lyons 2018; Xin and Chan 2020). Adaptive myelination occurs in the adulthood in zebrafish, rodents and humans in response to neuronal activity such as learning or sensory experience (Bacmeister et al. 2022; Braaker et al. 2025; Etxeberria et al. 2016; Gibson et al. 2014; McKenzie et al. 2014; Sampaio‐Baptista et al. 2013; Scholz et al. 2009; Steadman et al. 2020). OPCs can sense changes in neuronal activity through a plethora of different molecular mechanisms such as glutamatergic receptors (e.g., AMPA and NMDA), GABAergic receptors and voltage‐gated ion channels (Bergles et al. 2000; Cheli and Paez 2025; Kamen et al. 2025; Káradóttir et al. 2005, 2008; Kougioumtzidou et al. 2017; Kukley et al. 2007; Lin and Bergles 2004; Spitzer et al. 2019). In response to neuronal activity, OPCs differentiate into oligodendrocytes that deposit myelin in previously unmyelinated axonal segments tuning internodal length, nodal length and myelin thickness (Kaller et al. 2017). These changes support learning, fear conditioning, memory consolidation and reward learning, although it remains unclear whether these behavioural effects arise from changes in myelin itself, from other changes associated with oligodendrogenesis or from both (Bacmeister et al. 2022; McKenzie et al. 2014; Steadman et al. 2020; Yalçın et al. 2024). Thus, alterations in myelin plasticity may contribute to different neuropsychiatric disorders as it has been demonstrated for opioid addiction (Yalçın et al. 2024). Therefore, isolating activity‐instructed myelination from baseline myelination and a potential constitutive OPC differentiation programme and identifying the molecular mechanisms involved is essential to harness myelin plasticity for therapeutic gain.

The myelin‐independent circuit regulatory functions of OPCs stem from their direct interactions with neurons. During development, for example, first‐wave ventral OPCs can guide interneuron migration in the forebrain through contact repulsion mechanisms regulated by semaphorin‐plexin signalling, guiding interneurons away from blood vessels (Lepiemme et al. 2022). Additionally, OPCs can also directly form synapses with neurons throughout development and adulthood. Developmental OPCs form transient synapses with fast‐spiking interneurons that are lost in the early postnatal period (Orduz et al. 2015), while adult OPCs form synapses with both glutamatergic and GABAergic neurons (Bergles et al. 2000; Lin and Bergles 2004). These synapses may have three nonexclusive functions: instruct OPC fate, act as the activity‐sensing mechanism that guides myelination or feed outputs unrelated to myelin altogether. The evidence for the genuinely myelin‐independent outputs is growing. OPCs contact neuronal somata in an activity‐dependent manner and facilitate exocytosis of neuronal lysosomes, regulating neuronal metabolism and senescence (Fang et al. 2025). Similarly, in response to neuronal activity OPCs shed their surface proteoglycan NG2, which in turn modulates long‐term potentiation in somatosensory pyramidal neurons (Sakry et al. 2014). The cleanest separation of circuit regulation from myelination comes from regions where OPCs do not myelinate, such as the zebrafish optic tectum (Xiao et al. 2022; Xiao and Czopka 2023). In this region, OPC processes contact the axon arbour of retinal ganglion cell and genetic and pharmacological ablation of OPCs alters retinal ganglion cell axonal remodelling and visual processing (Xiao et al. 2022). Complementary work investigating the developing and adult mouse visual cortex has shown that OPCs surround axonal filopodia and internalise axon and presynaptic material in proportion to the synaptic remodelling required, implying roles for OPCs in synaptic and axonal pruning (Auguste et al. 2022; Buchanan et al. 2022, 2023).

These myelin‐independent functions require the same physical interaction with neurons that underlies activity‐sensing for myelination: OPCs tile the CNS parenchyma with an extensive, widespread network of processes (Barber et al. 2022; Hughes et al. 2013; B. B. Kirby et al. 2006), express a broad complement of neurotransmitter receptors and voltage‐gated channels that allow them to sense activity (Thornton and Hughes 2020) and form synapses with neurons (Bergles et al. 2000; Lin and Bergles 2004; Orduz et al. 2015). Therefore, a single manipulation typically perturbs both, myelinating and nonmyelinating circuit remodelling outputs of OPCs at once, limiting our capacity to separate these functions, an issue already highlighted in previous reviews (Xiao and Czopka 2023). As a result, the field cannot yet say what the neuron‐to‐OPC synapse is for, nor how OPC‐mediated pruning compares in weight to that of microglia and astrocytes (Chung et al. 2013; Paolicelli et al. 2011; Stevens et al. 2007; Xiao and Czopka 2023). Despite being unable to fully uncouple myelin‐independent and myelin‐depending functions of OPCs in circuit regulation, overall these results have reframed OPCs as neural circuit elements. Thus, determining whether and how this circuit regulation is altered in neurological and neuropsychiatric disorders is now a central question.

4. Vascular and Barrier Functions

OPC differentiation and myelination are energetically expensive, which makes close vascular interaction a necessity rather than an incidental feature as OPCs rely on the vasculature for nutrient supply (Yuen et al. 2014). This dependence shapes OPC interaction with blood vessels from development through adulthood and disease. During development OPCs arise from ventral and dorsal domains and migrate extensively along blood vessels, using them as a scaffold and detaching once they reach their destinations—a process guided by Wnt–C‐X‐C motif chemokine receptor type 4 (CXCR4) signalling (Tsai et al. 2016). However, OPCs do not merely use vessels for migration; they also shape vascularization. To meet the bioenergetic demands of developmental myelination, OPCs regulate white matter vascularization directly by contacting angiogenic tips in mouse, ferret and human and manipulating OPC numbers influences CNS vascularization (Chavali et al. 2020). While OPC depletion using a diphtheria toxin based genetic model leads to CNS hypovascularization, OPC expansion drives hypervascularization. These processes appear to be regulated by the expression of hypoxia‐inducible factor (HIF) and Wnt signalling pathways in OPCs, which in turn control endothelial cell proliferation (Chavali et al. 2020; Yuen et al. 2014). Once CNS vasculature is established, OPCs also play a role in the maintenance phase. OPCs contribute to barrier homeostasis supporting BBB integrity via transforming‐growth factor β (TGF‐β1) signalling (Seo et al. 2014).

The same relationship turns damaging in disease. In MS lesions, OPCs fail to detach from vessels and accumulate perivascularly, where their presence compromises both astrocyte endfeet and endothelial tight junction integrity, resulting in the loss of BBB integrity, increased vascular permeability and CNS inflammation (Niu et al. 2019). This defective detachment is mediated by aberrantly high Wnt signalling, which induces Wif1 secretion by OPCs, altering Wnt ligand‐mediated maintenance of endothelial tight junctions and further compromising BBB integrity (Niu et al. 2019). OPCs can also disrupt CNS vasculature and BBB through changes in extracellular matrix. For example, in white matter injury caused by prolonged cerebral hypoperfusion, matrix‐metalloprotease‐9 (MMP‐9) is upregulated and secreted by OPCs prior to demyelination thereby driving early BBB leakage and neutrophil infiltration (Seo et al. 2013).

Therefore, OPCs appear to have opposite roles in vascular regulation, building and maintaining the vasculature in the healthy CNS and disrupting this barrier in pathological contexts. This highlights the need for a model of OPC‐vascular niche interaction that identifies the underlying mechanisms regulating the switch from supportive to damaging and that establishes how far these interactions are held in humans. The obstacle to resolving this is as much technical as conceptual: OPCs, pericytes and perivascular fibroblast‐like cells share NG2 and PDGFRα expression and occupy the same perivascular niche, so cleanly attributing barrier and angiogenic effects to OPCs rather than their vascular neighbours remains a persistent difficulty.

5. Neuroimmune Functions

The close relationship of OPCs with the CNS vasculature also shapes their interaction with the immune system. Immune cells were long thought to reach the CNS parenchyma principally by diapedesis across the BBB, especially where it is damaged in disease (Greenwood et al. 2011). More recently, an expanding body of work has revised this view, revealing additional entry routes via the choroid plexus and the leptomeningeal and perivascular spaces and, most strikingly, vascular channels that connect the skull and vertebral bone marrow directly to the meninges and, under pathological conditions, to the CNS parenchyma (Rustenhoven and Kipnis 2022). Extensive work in the context of demyelination and MS that we and others have previously reviewed in detail (Cabeza‐Fernández et al. 2023; Zveik et al. 2024) demonstrates that innate and adaptive immune cells bidirectionally govern OPC fate. It is well‐established that myelin‐debris‐clearing macrophages and pro‐regenerative microglia, together with regulatory T cells, promote differentiation, while Th1, Th17 and CD8⁺T cell populations restrain it (Baxi et al. 2015; Bieber et al. 2003; Cantuti‐Castelvetri et al. 2018; Dombrowski et al. 2017; El‐Behi et al. 2017; L. Kirby et al. 2019; Kotter et al. 2005; Miron et al. 2013; Moore et al. 2015). However, over the past few years, growing evidence has demonstrated that OPCs themselves operate as immune sensors and effectors. As motile, surveying cells, OPCs react rapidly to injury and inflammation (Rhodes et al. 2006) and undergo transcriptomic changes that switch on a range of immune signals (Allen et al. 2023; L. Kirby et al. 2019; Medanha‐Falcao et al. 2018; Moyon et al. 2015). Through this transcriptional programme OPCs shape the inflammatory milieu directly, secreting cytokines and chemokines such as interleukin β (IL‐1β) and C‐C motif chemokine ligand 2 (CCL2), together with MMP9, which promote BBB opening and immune‐cell recruitment (Moyon et al. 2015; Seo et al. 2013). This output may initially aid pathogen clearance, yet OPCs also appear to restrain inflammation in this context as OPC depletion during lipopolysaccharide (LPS) challenge worsens microglial activation and neuronal damage (Liu and Aguzzi 2020; Nakano et al. 2017; S.‐Z. Zhang, Wang, et al. 2019). Whether the same immune competence is protective or harmful, however, depends on the context and duration of the inflammatory insult, a distinction that has come into focus with the characterisation of disease‐associated OPCs.

A pivotal step in establishing OPCs as immune regulators was the identification of immune or disease‐associated OPCs (DA‐OPCs). Single‐cell and spatial transcriptomic studies define the DA‐OPC state by rapid induction of disease‐associated markers such as Serpina3n, B2m and C4b alongside a coordinated immune programme spanning cytokine and chemokine release, immunoproteasome assembly and antigen‐processing and ‐presentation machinery. This upregulation has been described across MS and its rodent models, Alzheimer's disease, acute inflammatory challenges such as LPS and ageing (Allen et al. 2023; de la Fuente et al. 2020; Jäkel et al. 2019; Kenigsbuch et al. 2022; S.‐H. Lee et al. 2021; Medanha‐Falcao et al. 2018; Pandey et al. 2022). In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, this state emerges early, in the perivascular space and ahead of overt immune infiltration, consistent with induction by soluble mediators diffusing along a vascular gradient (Kukanja et al. 2024). Whether this state is a reversible response or a fixed identity is yet to be determined. Observations from our research group requiring additional validation indicate that LPS and polyinosinic:polycytidylic acid (Poly I:C)‐driven neuroinflammation, induces DA‐OPC marker expression only during active inflammation and that this expression is lost upon its resolution, pointing to this being a transient state (Cabeza‐Fernández et al. 2026). Critically, the DA‐OPC programme appears to be functionally double‐edged, because it equips OPCs with molecules that both restrain and amplify inflammation. In response to an inflammatory challenge—including exposure to cerebrospinal fluid from progressive MS patients—OPCs upregulate immune suppressive molecules such as the checkpoint ligands CD273 (PD‐L2) and CD274 (PD‐L1), enabling them to limit T‐cell‐driven and local inflammation and favour their own survival (Haile et al. 2015; Harrington et al. 2023; Kukanja et al. 2024; Medanha‐Falcao et al. 2018; Zveik et al. 2022). This immune regulatory mechanism has been suggested to be potentially permissive or beneficial for remyelination (Zveik et al. 2024). On the other hand, sustained interferon γ (IFNγ) and tumour necrosis factor (TNFα) exposure drives MHC‐I and MHC‐II expression, allowing OPCs to present antigen—including myelin‐derived antigen—to CD8⁺ and CD4⁺ T cells and thereby support T‐cell survival, activation and proliferation, establishing a feedforward cytokine loop that amplifies inflammation (L. Kirby et al. 2019; Medanha‐Falcao et al. 2018). Beyond classical antigen presentation, EAE studies coupled with OPC depletion implicate OPCs in actively sustaining inflammation and myelin damage through additional signalling pathways, with low‐density lipoprotein receptor‐related protein 1 (LRP1) and Wnt signalling identified as candidate mediators (Fernandez‐Castaneda et al. 2020; Q. Wang et al. 2025). The balance between these opposing outputs appears to be associated with disease chronicity: while DA‐OPCs may mitigate acute or early inflammation, under sustained challenge (e.g., in chronic EAE) they have been framed as drivers, or a nexus, of neurodegenerative progression (Castelo‐Branco et al. 2024; Zveik et al. 2024). One possible hypothesis stemming from these experiments is that the same immune programme that protects OPCs early upon inflammatory challenges may also be what diverts them from regeneration when inflammation becomes chronic, potentially both by competing with their regenerative functions as well as perpetuating the inflammatory environment that blocks remyelination.

An additional and still underexplored layer of OPC‐mediated immune regulation is the long‐lasting impact of inflammation on OPC epigenetics. Epigenetic inflammatory memory refers to the durable epigenetic imprints, or scars, that inflammation leaves on tissue resident cells, shaping how they respond to subsequent challenges (Naik and Fuchs 2022; Netea et al. 2020). Such memory has been documented for other glial cells, including astrocytes and microglia (H.‐G. Lee et al. 2024; Tiwari et al. 2024; Wendeln et al. 2018) and oligodendrocyte lineage cells appear to be no exception. In EAE, OPCs and mature oligodendrocytes retain enduring changes in chromatin accessibility uncoupled from transcription that may reflect epigenetic inflammatory memory (Meijer et al. 2022; Zheng et al. 2025), and neonatal OPCs mount a heightened inflammatory response when exposed to a second inflammatory challenge (Zheng et al. 2025), both supporting the notion of an epigenetic inflammatory memory in OPCs. Preliminary findings form our research group pending further validation, suggest that adult rodent OPCs can likewise acquire epigenetic inflammatory memory whose character depends on the inducing stimulus and which can in turn shape OPC immune and regenerative potential (Cabeza‐Fernández et al. 2026). This capacity to ‘store memories’ of previous encounters at epigenetic level may be conserved in OPCs across species, as human OPCs also show chromatin priming of developmental genes without expression that could shape their response to future stressors (Kabbe et al. 2026). Altogether these observations suggest that epigenetic inflammatory memory may act as an additional neuroimmune regulatory mechanism in OPCs, with potential implications for relapsing and chronic neurodegenerative disorders.

Defining the signals that induce, sustain and revert the DA‐OPC state, and its context‐dependent functions, is therefore a prerequisite for uncoupling the immune and regenerative functions of OPCs. Thus, increasing our understanding of how OPC immune functions compete with or enable myelin regeneration and identifying the molecular mechanisms behind OPC anti‐ and pro‐inflammatory functions and OPC inflammatory memory is essential to harness OPC neuroimmune functions for therapeutic gain.

6. Challenges: Heterogeneity and Ageing

Most of these novel myelin‐independent OPC functions have only recently been described and, in most cases, we are yet to identify the underlying mechanisms that regulate them and more importantly, to determine how they are altered across neurodevelopmental and neurodegenerative disorders. To better understand the role of these myelin‐independent OPC functions in disease we need to consider two challenges shared with canonical myelin‐dependent OPC roles: heterogeneity and ageing. Due to the recent emergence of noncanonical OPC functions, heterogeneity and ageing have so far been examined almost exclusively through the lens of myelination, leaving their relationship to the newly described OPC functions essentially unstudied and limiting our capacity to harness these functions to preserve CNS health.

The first challenge is heterogeneity. We are yet to determine whether distinct OPC subsets perform distinct noncanonical functions, amounting to a division of labour or whether a single plastic cell switches between functional states according to context; current data are compatible with both, and the field lacks agreed criteria to distinguish a stable subpopulation from an inducible state. Evidence from time‐lapse imaging suggests that some OPCs are more prone than others to differentiate into myelinating oligodendrocytes (Marisca et al. 2020) and the observation that a large fraction of adult OPCs never generate myelin raises the possibility that, while one subset performs myelinating functions, another may carry the nonmyelinating roles (Marisca et al. 2020; Xiao and Czopka 2023). This view has been challenged, however, by work indicating that adult OPCs are subjected to a constitutive differentiation programme, attempting to differentiate continuously and regularly across the CNS, a young‐adult behaviour that is impacted by ageing (Mironova et al. 2026). Adding further complexity, single‐cell RNA‐sequencing and, more recently, spatial transcriptomic experiments point towards a dynamic heterogeneity between OPC clusters that may be determined by the cells' microenvironment (Allen et al. 2023; Kukanja et al. 2024; Marisca et al. 2020; Marques et al. 2016, 2018). However, we lack robust markers for this degree of heterogeneity, which limits our capacity to perform lineage‐tracing studies that enable to determine the functional impact of these distinct OPC clusters. Lineage‐tracing and fate‐mapping studies have aimed to address the functional impact of developmental origin‐base OPC heterogeneity, but solely in the context of developmental myelination, adulthood myelination and remyelination (Crawford et al. 2016; Foerster et al. 2024; Kessaris et al. 2005; Tripathi et al. 2011), never for circuit regulation, myelin plasticity, neuroimmune regulation and vascular modulation. Likewise, regional diversity (e.g., white versus grey matter heterogeneity or brain versus spinal cord) has been investigated only in the context of myelination, not for the emerging myelin‐independent roles of OPCs (Bechler et al. 2015; Dimou et al. 2008; Viganò et al. 2013). Furthermore, the absence of markers to identify OPC subpopulations limits our capacity to determine whether human OPC heterogeneity mirrors that of rodents for both myelinating and nonmyelinating OPC functions. Collective efforts are therefore needed first to identify markers that allow lineage‐resolved functional investigation of OPC heterogeneity ideally across zebrafish, rodents and humans. This would enable dissecting heterogeneity in myelin‐independent and myelin‐dependent OPC functions and would help elucidating whether all OPCs or only a subset of OPCs is responsible for these different roles.

The second biggest challenge in the field is ageing. Ageing acts as a system‐wide stressor, making it difficult to disentangle intrinsic OPC ageing from a changing aged microenvironment or systemic age‐related changes impacting OPC function indirectly. Additionally, it is frequently unclear whether an age‐related change reflects a physiological decline of a normal function or the emergence of a reactive state (Salas et al. 2020). Almost all work on OPC ageing has concentrated on the intrinsic and extrinsic cues that limit OPC capacity to form new myelinating oligodendrocytes and the mechanisms underlying age‐associated remyelination impairment (Neumann, Baror, et al. 2019; Neumann, Segel, et al. 2019; Neumann et al. 2020; Ruckh et al. 2012; Segel et al. 2019; Shields et al. 2000; Sim et al. 2002). Bulk and single cell transcriptomic, proteomic and spatial transcriptomic studies have started to shed light into how ageing may affect other OPC functions. With age OPCs not only decrease their regenerative capacity but also become predominantly quiescent, upregulate immune or disease‐associated and phagocytic gene expression and acquire senescent markers (Allen et al. 2023; de la Fuente et al. 2020; Heo et al. 2025; Neumann, Baror, et al. 2019; Segel et al. 2019; Spitzer et al. 2019; Ximerakis et al. 2019). Although OPCs were originally thought to resist replicative senescence (Tang 2001), more recent studies show that aged rodent OPCs and directly reprogrammed human oligodendroglia upregulate the senescence markers p16/Cdkn2a and p21/Cdkn1a and acquire a senescence‐associated secretory phenotype (SASP) (Gomez et al. 2024; Neumann, Baror, et al. 2019; Windener et al. 2024), similar to what has been described in disease settings such as MS and Alzheimer's disease (Nicaise et al. 2019; Papadopoulos et al. 2025; P. Zhang, Kishimoto, et al. 2019). While these transcriptomic and phenotypic changes suggest that the noncanonical functions of OPCs are themselves dysregulated with age, no functional studies have yet addressed how ageing affects OPC circuit regulation, OPC–vascular interaction or OPC immune function. Notably, these intrinsic changes appear largely coupled to the ageing microenvironment. Rejuvenating the aged CNS niche by heterochronic parabiosis, young CSF infusion or metformin, restores the differentiation, myelin maintenance and remyelinating capacity of aged OPCs (Iram et al. 2022; Neumann, Baror, et al. 2019; Ruckh et al. 2012). Most strikingly, aged OPCs transplanted into the neonatal CNS rejuvenate their transcriptome and proliferate and differentiate like resident neonatal OPCs (Segel et al. 2019). This indicates that age‐related functional decline in OPCs is probably better understood as a response to the aged environment than as a cell‐autonomous programme. However, whether all other OPC functions are equally restored in aged OPCs when exposed to a youthful environment is still to be elucidated. Furthermore, ageing also affects OPC heterogeneity unevenly. For instance, developmental origin shapes how OPC regenerative capacity declines with age, with this decline more pronounce in dorsally than ventrally derived OPCs (Crawford et al. 2016). This may relate to the greater vulnerability of dorsal OPCs to DNA damage, a key hallmark and driver of ageing and senescence, relative to ventral OPCs (Boda et al. 2022). Region‐based heterogeneity is also differentially impacted by ageing as OPCs become more regionally diverse with age (Spitzer et al. 2019) and age‐associated myelin dysregulation, myelin loss and myelin‐damage‐associated inflammation fall predominantly in the white matter (Bowley et al. 2010; Dimovasili et al. 2023; Groh and Simons 2025; Hill et al. 2018; Kaya et al. 2022; Qian et al. 2020; Safaiyan et al. 2016, 2021; Wang et al. 2020). Thus, age‐related vulnerability is not distributed evenly across OPC populations, increasing the complexity of the age‐related functional impact on OPCs. Additionally, if the aged OPC phenotype is principally driven by the environment rather than intrinsically fixed, it remains unknown whether different OPC subsets are equally susceptible to the ageing CNS niche or whether the balance of intrinsic and extrinsic influence is weighted differently across OPC subsets. Despite the technical difficulty of working with ageing cohorts, concerted efforts are needed to map how the full range of OPC functions is shaped across life, drawing parallels between development, adulthood and ageing, so that the susceptibility of both myelin‐dependent and myelin‐independent functions to age‐related decline can be understood.

7. Conclusions

The same features that allow OPCs to myelinate and remyelinate (ubiquity, motility, sensitivity to neuronal activity and persistence throughout life) also underpin a repertoire of functions that, until recently, went unrecognised in a cell studied almost solely as a progenitor of myelinating oligodendrocytes. These noncanonical roles reframe the OPC as a cell positioned at the intersection of myelination, circuit function, immunity and the vasculature. This multifunctionality enhances the therapeutic appeal of OPCs, but it also complicates it, as interventions designed around one function may also modulate the others. Before this functional repertoire can be harnessed for therapeutic gain, concerted efforts are required to close several knowledge gaps: which functions are intrinsic to OPCs and which are inducible OPC states, whether these functions are shared by all OPCs or divided among subsets and how ageing and disease reshape each of these roles. Additionally, identifying the molecular mechanisms regulating the different OPC functions will reveal whether each function can be modulated independently of the others. Closing these gaps will require markers that permit functional tracing of OPC heterogeneity across zebrafish, rodents and humans, together with a deliberate effort to map each OPC function and its regulatory mechanisms across development, adulthood and ageing. Only then will it be possible to say which of these roles fail in disease and which might be preserved or restored.

Author Contributions

Alerie G. de la Fuente: conceptualization, funding acquisition, writing – original draft, writing – review and editing.

Funding

This work was supported by the Ministerio de Ciencia Innovación y Universidades, Agencia Estatal de Investigación (PID2024‐161979OB‐I00 and CEX2021‐001165‐S) and the Generalitat Valenciana (CIPROM/2022/15).

Disclosure

During the preparation of the manuscript the author used Claude to revise English grammar and usage. After using this tool, the author reviewed and edited the content and take full responsibility for the content of the publication.

Conflicts of Interest

The author declares no conflicts of interest.

APPENDIX

I obtained my PhD in Clinical Neurosciences at the University of Cambridge, under the supervision of Prof. Robin Franklin, where I discovered OPCs and trained in oligodendrocyte lineage cells and CNS myelin biology. My PhD focused on the role of nuclear receptors in OPC differentiation, myelination and remyelination. For my postdoctoral studies I stayed in the same laboratory, captivated by the world of OPCs and myelin, and turned to how ageing impairs OPC regenerative capacity. Two early‐career fellowships aimed at supporting the transition to independence then took me to Queen's University Belfast, where I joined Prof. Denise Fitzgerald's group and trained in neuroimmunology. There I learned about the interplay between the CNS and the adaptive immune system, focusing on the crosstalk between OPCs and T cells and how ageing shapes it. In 2022 I started my own research group at the Institute of Health and Biomedical Sciences of Alicante, and in 2025 I moved as a principal investigator to the Institute of Neuroscience CSIC‐UMH. My group investigates the molecular, cellular and systemic mechanisms that regulate myelin formation, maintenance and regeneration in the CNS, with a particular focus on the interaction between oligodendrocyte lineage cells and inflammation, to understand myelin alterations and remyelination failure in CNS pathologies such as MS.

• 1What led you to become a neuroscientists?

Probably watching my grandmother age and seeing how her brain and cognitive abilities changed as she grew older. I had always been fascinated by the brain and how it controls such complex cognitive and emotional behaviour, but seeing those abilities gradually lost in someone who had always been my reference made me wonder whether brain ageing could be slowed, or even stopped. During my biology degree we were taught that neurons in the CNS do not regenerate, and when I began thinking about a PhD, I came across the work of the person who would later become my supervisor, and learned that myelin, a part of the CNS, could in fact regenerate. After years of hearing that the CNS does not repair itself, I found this idea genuinely puzzling, and over time myelin regeneration became the centre of my scientific career.

• 2What did you learn during your PhD/postdoc that helped you launch your independent career?

Surprisingly, my two supervisors shared very similar approaches to science. Whenever I came to them with an experiment or an idea, both would answer with the same question: what is the question you want to address? From them I learned that the most important part of a project is the initial question. Framing a clear question, one you are genuinely curious about or that you feel needs resolving, is what lets you build a project and then choose the experimental approaches to answer it. I was always focused on the “how”, and both of them showed me that before the “how” it is essential to spend far more time thinking about the “what”.

I also learnt to focus my energy, to go deep rather than wide, and to set priorities. When I started my PhD, my enthusiasm was a double‐edged sword: it kept me going and helped me getting lots done, but it also scattered my thinking and led me to spread myself thin. They both helped me channel that enthusiasm and organise my priorities, something I find essential now, at the start of an independent career, with all the new roles it brings. I am still learning how best to do this, but without their efforts to help me focus during my PhD and postdoc, it would be a far more daunting task.

• 3What external influences or mentors had a significant impact on your scientific career?

My PhD supervisor, Prof. Robin Franklin, and my fellowship supervisor, Prof. Denise Fitzgerald, were both instrumental at every stage of my career, and remain so today in my role as a group leader. Both are inspiring scientifically and personally, and I would never have become a principal investigator, or kept my passion for science, without them. Having truly supportive mentors, people you can keep learning from and turn to at important decisions and turning points, is essential to making this step and navigating the transition. I am very lucky to still count on their advice. Endless career and scientific discussion with them, who know my strengths and weaknesses, has helped me find my own niche, and although their supervision styles were and are different, Robin and Denise are my references and clearly shaped the kind of scientist and mentor I hope to become.

I have also been fortunate with other colleagues and senior peers along the way. Dr. Elena Marcello was the first postdoc who mentored me before my PhD, and her enthusiasm and her approach to science convinced me to pursue my PhD. Dr. Francisco Rivera, a long‐standing collaborator, has not only been a great friend and fantastic person with whom debate science and think projects, but also a source of support in dealing with the inevitable rejections that feed impostor syndrome. More recently, when I moved back to Spain after spending my whole scientific career in the UK, Dr. Berta López was instrumental in helping me navigate the Spanish system and settle into my new role. I have been extremely lucky to meet many more colleagues than I could name here who have advised and supported me at different stages. One key lesson from both of my supervisors was to build a scientific network beyond them and my immediate peers, advice that has given me a wide and genuinely supportive network throughout my career.

• 4What are the main challenges young neuroscientists face to build an independent and successful career in research? How did you overcome those? Do you have any tips you'd like to share with early‐career scientists based on your personal experience?

To be honest, I am not sure I have overcome them yet. For me, the biggest challenges were and still are: 1) adjusting to the new role, 2) hiring the right team, and 3) dealing with rejection and impostor syndrome.

Once you become independent, your role changes completely: you go from the bench, focused on experiments and results, to a managerial position with far more responsibility and almost no training for it. I was lucky that Denise eased my transition by giving me an increasingly managerial role during my fellowship, so the jump was less abrupt but even so, the accumulation of tasks, and the responsibility of now being the person behind other people's scientific careers, can be very stressful.

As a postdoc you are the main driver of the experiments and the output; as a PI you rely entirely on your team, and therefore on your ability to choose people who match your goals and way of working. Here I was extremely lucky. My first PhD student, Sonia Cabeza, and my lab manager, Angela Armengol, are absolute stars. We share a work ethic, goals and a way of solving problems, and together we have built exactly the atmosphere I hoped for my research group: supportive, trusting and hardworking, but also genuinely enjoyable.

The third challenge was handling rejection while keeping my own impostor syndrome in check. Rejections are inevitable as funding is limited and success rates are low, but when you are starting a group, funding is essential for stability and for keeping your team, which raises the pressure enormously. Grant writing also demands a set of skills you do not necessarily acquire as a postdoc, and you learn as you go. Therefore, it is almost inevitable to struggle at first, especially before you have found your niche and understood the different funding schemes. That uncertainty is stressful and feeds self‐doubt, and although everyone faces it regardless of career stage, I think it hits new group leaders hardest. It is hard to give universal advice, since everyone copes differently, but what has worked for me is to talk to peers and senior colleagues and to lean on my network and mentors when I feel lost. The scientific community is, on the whole, remarkably generous, and almost everyone faces the same hurdles when starting out, which is exactly why talking about them has so often helped.

• 5There is an important movement to change the current system to evaluate research output and research career. What is your view? Any suggestion to improve the current system?

This is a difficult question, and I do not have a clear solution, but a few things seem worth changing. Limited funding worldwide, the debate around metrics and impact factor, and the constant arrival of new techniques that quickly become expected by journals all place a heavy burden on the community, and especially on researchers starting their own groups. In the early years you usually work with limited funding and few people until you establish your niche, and even with an excellent question, it takes time to generate results and to understand what they mean. Yet most funding schemes cover only short periods — typically two to four years — which rarely allows a research question to reach its full potential.

Two changes could potentially help. First, evaluation could weigh outputs against the human and financial resources actually available, rather than in absolute terms; experience and years of independence are often considered, but limited resources are not weighted enough. A fairer way to measure the relevance of outputs relative to the resources behind them would ease some of the pressure on new group leaders. Second, longer funding periods (for example, five years, as with ERC projects, with budgets scaled accordingly) would benefit everyone, but particularly those at the start of independence, giving them the time to build a group and develop a substantial body of work. Neither change is simple given current funding constraints, but I believe both would help relieve pressure on early‐career scientists.

de la Fuente, A. G. 2026. “Rethinking the Oligodendrocyte Progenitor Cell: One Cell, Many Functions.” European Journal of Neuroscience 64, no. 7: e70676. 10.1111/ejn.70676.

Data Availability Statement

Data sharing does not apply to this article as no new data were created or analysed in this study.