Crosstalk Between Oligodendrocyte Lineage Cells and CNS‐Resident and Peripheral Immune Cells Governs Demyelination and Remyelination in Multiple Sclerosis

ABSTRACT

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by immune‐mediated attacks on myelin produced by oligodendrocytes (OLs). Oligodendrocyte precursor cells (OPCs) and mature OLs are CNS cell types essential for generating myelin sheath, which supports saltatory conduction and neuronal metabolic support. Although the roles of CNS resident cells (neurons, microglia, astrocytes) and peripheral immune cells in MS pathogenesis are well established, our understanding of how oligodendrocyte lineage cells (OLCs)—comprising OPCs and mature OLs—bidirectionally interact with these cell types to influence disease progression remains incomplete. Emerging evidence emphasizes the critical role of disease‐associated OLCs in neuroimmune responses and their underlying signaling mechanisms. Therefore, elucidating how pathological environments shaped by CNS and peripheral cells influence OLC function may identify critical therapeutic targets for promoting remyelination and recovery in MS. This review synthesizes current knowledge of OLC biology in health and disease, with emphasis on complex intercellular interactions that determine demyelination, remyelination, and axonal integrity in MS.

• Unwanted interactions of oligodendrocyte lineage cells with multiple cell types are seen in demyelinating diseases.

• Intervening these interplays may provide therapeutic strategies for multiple sclerosis.

Abbreviations

ABCA1/G1

ATP‐binding cassette transporter A1/G1

AD

Alzheimer's disease

ADCC

antibody‐dependent cellular cytotoxicity

ALS

amyotrophic lateral sclerosis

APCs

antigen presenting cells

BBB

blood–brain barrier

BCSFB

blood cerebral spinal fluid barrier

BDNF

brain‐derived neurotrophic factor

BLMB

blood‐leptomeningeal barrier

C1q

complement component 1q

CAL

chronic active lesion

CCL

C‐C motif chemokine ligand

CCR

C‐C chemokine receptor type

CDC

complement‐dependent cytotoxicity

Cdk5

cyclin‐dependent kinase 5

Clcf1

cardiotrophin‐like cytokine 1

CNS

central nervous system

CNTF

ciliary neurotrophic factor

CP‐AMPA

calcium permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolpropionic acid

CPZ

cuprizone

CSF

cerebrospinal fluid

CSF1R

colony stimulating factor‐1 receptor

CSPGs

chondroitin sulfate proteoglycans

Cx

connexin

CX3CR1

C‐X3‐C motif chemokine receptor 1

CXCL

chemokine (C‐X‐C motif) ligand

DICAM

dual immunoglobulin (Ig) domain containing cell adhesion molecule

dMBP

degraded myelin basic protein

EAE

experimental autoimmune encephalopathy

ECM

extracellular matrix

EDIL3

EGF‐like repeats and Discoidin domains 3

FasL

Fas ligand

FGF

fibroblast growth factor

GABA

glutamatergic and gamma‐aminobutyric acid

GFAP

glial fibrillary acidic protein

GLUT1

glucose transporter 1

GM‐CSF

granulocyte/macrophage colony‐stimulating factor

GPCR

G‐protein coupled receptor

GSH

glutathione

HIF‐1

hypoxia inducible factor‐1

hiPSCs

human induced pluripotent stem cells

HMGB1

high mobility group box 1

HO‐1

heme oxygenase‐1

Iba‐1

ionized calcium‐binding adapter molecule 1

ICAM‐1

intracellular adhesion molecule‐1

IFN‐γ

interferon‐γ

IGF

insulin‐like growth factor

IL‐1Ra

IL‐1 receptor antagonist

iNOS

inducible nitric oxide synthase

LCN2

lipocalin‐2

LFA‐1

leukocyte function‐associated antigen‐1

LIF

leukemia inhibitory factor‐like protein

LINGO‐1

leucine‐rich repeat and immunoglobulin‐like domain‐containing Nogo receptor‐interacting protein‐1

LPS

lipopolysaccharide

LRP2

lipoprotein receptor‐related protein 2

MAG

myelin‐associated glycoprotein

MBP

myelin basic protein

MCTs

monocarboxylate transporters

MERFISH

multiplexed error‐robust fluorescence in situ hybridization

mGLURs

metabotropic glutamate receptors

MHC

major histocompatibility complex

MiDMs

microglia‐derived macrophages

MoDMs

monocyte‐derived macrophages

MOG

myelin oligodendrocyte glycoprotein

MS

multiple sclerosis

mtDNA

mitochondrial DNA

Myrf

myelin regulatory factor

NF‐κB

nuclear factor κ‐light‐chain enhancer

NK

natural killer

NMDA

N‐methyl‐D‐aspartate

NMDARs

N‐methyl‐d‐aspartate receptors

NOTCH1

neurogenic locus notch homolog protein 1

NR‐1

neuregulin‐1

Nrf2

nuclear factor erythroid‐2‐related factor 2

NRG1

neuregulin‐1

NSCs

neural stem cells

NT‐3

neurotrophin‐3

OLCs

oligodendrocyte lineage cells

OLs

oligodendrocytes

OPCs

oligodendrocyte precursor cells

PDGF

platelet‐derived growth factor

PLP

proteolipid protein

ROS

reactive oxygen species

SASP

senescence‐associated secretory phenotype

SIRT2

sirtuin 2

SVZ

subventricular zone

Tc

cytotoxic T

TCR

T‐cell receptor

TGF‐β

transforming growth factor‐beta

Th

T helper

TNF‐α

tumor necrosis factor‐alpha

TREM2

myeloid cells 2

VCAM‐1

vascular cell adhesion molecule‐1

VEGF‐A

vascular endothelial growth factor A

VLA‐4

very late antigen‐4

Wif1

Wnt inhibitory factor 1

1. Introduction

Multiple sclerosis (MS), a chronic CNS autoimmune and neurodegenerative disorder, features multifocal demyelination, neuroinflammation, and progressive axonal degeneration (Lassmann 2018). This pathology centers on immune‐mediated destruction of oligodendrocytes (OLs)—the CNS myelinating glia (Traka et al. 2016). Myelin loss disrupts circuit connectivity, culminating in irreversible axonal and neuronal degeneration (Dutta and Trapp 2011; Anan'ina et al. 2020).

Recent decades have elucidated the core transcriptional and epigenetic machinery governing OL differentiation and myelination (Emery 2010). Integrative transcriptomic analyses of human MS lesions reveal that OLs undergo disease‐associated transcriptional reprogramming, adopting distinct stress‐ and immune‐responsive states within the inflammatory microenvironment (Yan et al. 2025). Single‐nucleus RNA sequencing further demonstrates extensive ligand‐receptor signaling interactions between OLCs and activated microglia, underscoring the importance of intracellular communication networks in shaping lesion pathology (Yan et al. 2025).

Although MS pathogenesis mechanisms remain incompletely defined, immune cell‐mediated attacks emerge as the primary driver of demyelination and remyelination failure (Groppa et al. 2021). Beyond direct OL/myelin destruction, the MS inflammatory milieu impairs surviving OL metabolic support and blocks OPC recruitment, proliferation, and differentiation (Liu et al. 2021; Blaszczyk et al. 2025). Chronic inflammation and inhibitory factors, contributed altogether by immune cells and neural cells in MS lesions, render a hostile environment, impairing OPC proliferation, migration, and differentiation into mature myelinating OLs (Zveik et al. 2024). This failure of endogenous remyelination results in persistent demyelination, axonal dysfunction, and irreversible neurodegeneration, hallmarks of disease progression and disability in MS patients. Elucidating the molecular and cellular interactions between oligodendrocyte lineage cells (OLCs) and other cell types in MS will provide crucial insights into therapeutic designs aiming to reduce OL/myelin injury and enhance OL regeneration and remyelination, a currently unmet need in clinical MS therapies. This review synthesizes OLC interactions with neurons, astrocytes, microglia, and adaptive/peripheral immune cells across the MS disease course. We evaluate how these cellular crosstalk networks drive OL injury, suppress repair, and identify therapeutic opportunities to restore myelin regeneration.

2. OLC Biology: Proliferation, Differentiation, Myelination, and Its Regulation

Mature OLs derive from OPCs originating from ventral neuroepithelial progenitors within periventricular zones. Olig2 and Sox10 orchestrate OPC lineage specification and terminal differentiation (Emery 2010). In the murine CNS, OPCs are generated in three developmental waves: a ventral wave from embryonic day 9.5 (E9.5), a subsequent dorsal migration, and a postnatal dorsal SVZ‐derived wave (Fancy et al. 2009; Kessaris et al. 2006). In the forebrain, OPCs initially emerge ventrally (E12.5), shift dorsally (E15.5), and later arise from the SVZ, which initiates as early as E17.5 before expanding postnatally (Winkler et al., 2018). By P10, ventral‐derived OPCs are largely replaced by medial and dorsal populations (Kuhn et al. 2019; van Tilborg et al. 2018).

OPCs progress through pre‐myelinating stages to mature OLs via integrated transcriptional, epigenetic, and axonal signaling cascades (Figure 1). This trajectory features G1 arrest, process extension, and activation of myelin structural genes (MBP, PLP, MAG) (Zuchero and Barres 2013; Emery and Lu 2015). Olig2 specifies OL lineage (Kuspert et al. 2011), Sox10 maintains OL identity (Emery and Lu 2015), and Myrf activates myelin gene expression (Bujalka et al. 2013), while T3 signaling further promotes OPC differentiation and enhances the expression of myelin‐related genes (Lee and Petratos 2016). In addition, a study reported that PDGF promotes OPC motility through Cdk5, with Fyn cooperating in activation and motility control, indicating co‐activators beyond p35/p39 (Miyamoto et al. 2008). Mature OLs extend processes to enwrap axons, forming myelin sheaths that support saltatory conduction and neuronal activity (Osso and Hughes 2024). Axonal signals, including neuregulin (NRG), neuronal activity, and ECM interactions play a fundamental role in guiding OL differentiation and myelin formation, initiating in spinal cord at birth and peaking in cortical regions during postnatal Weeks 2–4 (Lundgaard et al. 2013; Baumann and Pham‐Dinh 2001; Cristobal and Lee 2022). The prefrontal cortex is among the last regions to complete myelination, continuing into early adulthood (Sousa et al. 2018). Although developmentally programmed, myelination remains plastic across life, influenced by neuronal activity and experience (Monje 2018). GABAergic signaling via NMDA and GABA receptors on OPCs modulates OPC proliferation and differentiation (Wake et al. 2011), while environmental enrichment and learning enhance OL proliferation and myelin thickness (Scholz et al. 2009). Dysregulated OL differentiation and myelination contributes to disorders such as MS, leukodystrophies, schizophrenia, and major depressive disorder (Takahashi et al. 2011). In MS, chronic inflammation hampers OPC recruitment, differentiation, and remyelination (Franklin and Ffrench‐Constant 2017); thus, therapies promoting OPC differentiation (e.g., thyroid hormone analogs, Leucovorin/Dyclonine) have been suggested (Hartley et al. 2019; Hure et al. 2024).

FIGURE 1.

Oligodendrocyte lineage cells in health and pathological conditions. Under healthy conditions, neural stem cells differentiate into OPCs through the regulation of Sox10 and Olig2. Newly generated OPCs migrate to their target sites, facilitated by PDGF, Fyn, and Cdk5. OPCs then differentiate into OLs under the influence of T3 and GABA signaling, NRG, and Sox10. Finally, pre‐OLs mature into fully functional OLs through the activation of NRG and Myrf. In pathological conditions, processes governing OPC development and OL maturation are disrupted by various pathological factors, including ROS, inflammation, and glutamate excitotoxicity. Migration of OPCs is suppressed by altered chemokine/chemokine ligand, CSPG, and Wif1, and differentiation of OPCs is inhibited by IFN‐γ and pro‐inflammatory cytokines. These outcomes and pathological factors contribute to OLs' apoptosis, remyelination failure, and the formation of myelinosomes.

3. Oligodendroglia Pathology in MS in the Aspect of OL Damage/Injury, Survival, Demyelination, Regeneration and Remyelination Failures

The pathophysiology of MS involves several key mechanisms, including direct OL damage, demyelination, and remyelination failure. This section provides a brief discussion of these pathological processes depending on the different pathological mechanisms, incorporating the latest research findings to help readers understand the consequences of OL pathology in MS.

3.1. Direct OL Damage and Demyelination

OL death arises through oxidative/mitochondrial stress, glutamate excitotoxicity, and adaptive immune attack (Lei and Lin 2024). Microglia and autoreactive leukocytes generate ROS/RNS that trigger mitochondrial fission, membrane depolarization, and bioenergetic collapse in OLs (Lei and Lin 2024). MS lesion OLs harbor high mtDNA mutation burdens that impair respiratory chain complexes, driving caspase‐dependent apoptosis and depriving axons of lactate metabolic support (Lei and Lin 2024; Campbell et al. 2011). Excess glutamate overactivates CP‐AMPA/NMDA receptors on OLs, raises intracellular Ca2⁺ in OLs, and hinders subsequent repair (Zonouzi et al. 2011; Evonuk et al. 2020). Cytotoxic CD8+ T cells damage OLs via granzyme and complement pathways (Shi et al. 2023), while early lesion formation also reflects strong innate activation such as microglia (van den Bosch et al. 2024). Antibodies to MOG, MBP, and PLP promote antibody‐dependent cellular cytotoxicity (ADCC) (Reindl et al. 1999; Greer et al. 2020; Peschl et al. 2017), complement‐dependent cytotoxicity (CDC), and Fc receptor‐mediated myelin phagocytosis (Peschl et al. 2017; Abdul‐Majid et al. 2002); C1q/C3b deposition and MAC formation disrupt OL membranes and trigger death, findings that have been corroborated by immunohistochemical analyses of human MS lesion tissue (Watkins et al. 2016; Ingram et al. 2014). In ADCC, NK cells, macrophages, and microglia engage Fcγ receptors (FcγRs) to release perforin/granzyme, and depletion of FcγR+ effectors reduces OL injury in EAE (Shi et al. 2023; Vedeler et al. 2001; Voskoboinik et al. 2015; Szalai et al. 2005), although the causal contribution of this pathway in human MS lesions has not been directly established. Similarly, effector damage depending on FcRγ, and loss of inhibitory FcγRIIb biasing toward autoimmunity, are supported primarily by experimental and general immunological evidence (Baerenwaldt and Nimmerjahn 2008; Nimmerjahn and Ravetch 2008); direct validation in human MS tissue remains limited.

3.2. Early OL Injury and Axonal Vulnerability

Whether OL injury initiates at the soma versus myelin sheath—and the causal directionality—remains unresolved (Lucchinetti et al. 2000; Romanelli et al. 2016). Metabolic stress, oxidative injury, and excitotoxicity can precede heavy leukocyte influx and large‐scale demyelination (Lopez‐Muguruza and Matute 2023; Pernin et al. 2022). ROS destabilizes myelin and is associated with myelinosome budding and release, which can amplify inflammatory signaling and aggravate axon damage (Romanelli et al. 2016; Lopez‐Muguruza and Matute 2023). The formation and release of myelinosomes may contribute to the amplification of inflammatory signaling and exacerbation of axonal and neuronal degeneration, representing a critical early step in MS lesion evolution (Romanelli et al. 2016). Understanding these mechanisms highlights potential therapeutic targets, such as preserving OL metabolism, mitigating inflammatory responses, and stabilizing myelin integrity, to interrupt the cycle of damage in MS lesions. In inflammatory settings, loss of OL metabolic support renders myelinated axons unusually fragile—often more so than unmyelinated fibers—underscoring the value of preserving OL metabolism early in disease (Lopez‐Muguruza and Matute 2023; Pernin et al. 2022; Schaffner et al. 2023). These findings suggest that therapeutic approaches aimed at preserving OL metabolism could play a crucial role in maintaining axonal integrity during the early stages of MS, before extensive demyelination occurs.

3.3. Remyelination Impairment

Effective repair requires timely OPC recruitment to denuded axons and their maturation into myelinating OLs; MS disrupts both phases (Garton et al. 2024) (Figure 1). Under pathological conditions, such as oxidative stress, inflammation and excitotoxicity (Romanelli et al. 2016; Lopez‐Muguruza and Matute 2023; Pernin et al. 2022), OPC migration, differentiation and myelination are impeded, thereby leading to OL impairment (Spaas et al. 2021; Zhang et al. 2024; Deng et al. 2004). In demyelinated lesions, chondroitin sulfate proteoglycans (CSPGs)‐rich ECM interacting with OPC surface receptors creates a non‐permissive substrate that impedes cell migration (Ghorbani and Yong 2021). Chemokine guidance is perturbed: altered chemokines such as CXCL12 gradients that play a crucial role in OPC recruitment blunt lesion homing (Dziembowska et al. 2005; de Castro et al. 2013). Another pivotal study demonstrates that vascular interactions also go awry, resulting in perivascular OPC retention driven by aberrant Wnt signaling and Wnt inhibitory factor 1 (Wif1) secretion, which destabilizes endothelial junctions and astrocytic end‐feet, worsening blood–brain barrier (BBB) dysfunction and inflammation in experimental demyelination models (Niu et al. 2019). This defective interaction between OLs and the vasculature suggests that abnormal OPC migration not only hinders their recruitment to demyelinated lesions but also perpetuates demyelination pathology by disrupting the BBB and exacerbating inflammation. While these findings provide mechanistic insight into how Wnt dysregulation may impair OPC recruitment, direct evidence for this vascular Wnt signaling axis in human MS lesion remains to be established. Even when OPCs arrive, inflammatory cues stall differentiation. Interferon (IFN)‐γ drives an immune‐like OPC state with MHC expression that slows maturation; IFN‐β and dimethyl fumarate counter this program (IFN‐β suppresses MHC II; DMF suppresses MHC I/II) (Jank et al. 2024; Kirby et al. 2019). IFN‐γ‐induced MHC I further licenses CD8+ T cell activation and OPC death (Jank et al. 2024). High oxidative load and dysregulated cholinergic signaling impose additional brakes on OL differentiation and repair (Ravichandar et al. 2024; French et al. 2009). Moreover, depending on the lesion type, the status of OLCs varies significantly, influencing the overall remyelination process (Garton et al. 2024; Zhao and Jacob 2023). For instance, the number of OLs remains consistent with the normal condition and remyelination is detected in early active lesions (Garton et al. 2024; Zhao and Jacob 2023). Furthermore, activated microglia and monocyte‐derived macrophages, meningeal T cells, and B cell‐linked inflammation create cytokine milieus that drive OL demyelination and death, ultimately amplifying neuronal injury (Zhao and Jacob 2023; Lucchinetti et al. 2011). Building on this, the next section will summarize how OLCs interact with CNS resident cells and infiltrating immune cells in the context of MS.

3.4. Adaptive Resilience, Survival, and Metabolic Adaptation of Oligodendrocytes in Chronic MS Lesions

While OL dysfunction and programmed cell death remain central hallmarks of MS pathogenesis, emerging evidence underscores a remarkable degree of adaptive resilience, metabolic plasticity, and transcriptional heterogeneity among OLs within chronic or inactive lesions. Recent snRNA‐seq and spatial transcriptomic analyses of post‐mortem human MS brains have challenged the traditional view that mature OLs are uniformly vulnerable to the neuroinflammatory environment (Schirmer et al. 2019). These transcriptomic analyses indicate that subsets of mature OLs persist within chronic MS lesions exhibiting stress‐associated molecular signatures, including the upregulation of cytoprotective pathways and heat shock proteins, suggesting the existence of adaptive oligodendroglial states rather than uniform degeneration (Schirmer et al. 2019).

Landmark single‐cell RNA sequencing studies identified that MS‐specific disease‐associated OLC subpopulations—including immunoresponse‐OLs and myelin‐forming OLs with stress‐responsive transcriptional programs—arise selectively in MS lesion tissue compared to healthy controls, establishing that the inflammatory CNS environment actively reprograms OLC identity rather than causing uniform degeneration (Falcao et al. 2018). Moreover, these advanced profiling techniques have identified various OL subpopulations with proportionally diminished stress‐responsive subpopulations and increased immune‐related OL subpopulations depending on the inflammatory milieu and the lesion status in MS (Jakel et al. 2019). These findings indicate that OL populations react in a heterogeneous manner, with each subtype showing distinct resilience and survival abilities (Jakel et al. 2019).

‘Pandey et al. showed that disease‐associated OLC responses are shared across multiple neurodegenerative diseases, further supporting the concept of a conserved OLC pathological response program (Pandey et al. 2022). In this study, a cross‐disease single‐cell transcriptomic analysis demonstrated that a core set of disease‐associated OLC markers—overlapping substantially with the immunoresponse‐OL and stress‐response populations identified in MS—are recapitulated in ALS, AD, and other CNS pathologies, suggesting that OLCs mount a stereotyped transcriptional response to diverse neuroinflammatory and neurodegenerative stimuli (Kenigsbuch et al. 2022). These cross‐disease findings carry important implications: they suggest that therapeutic strategies targeting disease‐associated OLC states in MS may have broader applicability, while also underscoring the need to identify MS‐specific modifiers that distinguish the oligodendroglial response in the autoimmune demyelinating context from that in other neurodegenerative conditions.

In addition, emerging evidence suggests that surviving OLs undergo adaptive responses in chronically demyelinated environments (Jakel et al. 2019; Zheng et al. 2025). Importantly, these observations are consistent with the presence of partially remyelinated “shadow plaques” in chronic MS tissues, supporting the notion that a subset of OLs survives longstanding inflammatory injury and retains limited endogenous reparative potential. This residual reparative capacity is not solely constrained by cell‐intrinsic OL limitations; spatial transcriptomic profiling of post‐mortem MS brain tissue has revealed that senescence‐like transcriptomic signatures in glial cells extend from lesion cores into periplaque white matter regions, indicating that OLs residing outside the demyelinated core are exposed to a SASP‐enriched, repair‐suppressive microenvironment (Pandey et al. 2022; Gross et al. 2025). Moreover, low‐level senescence markers are detectable within OLs themselves, alongside the dominant senescence burden in microglia (Pandey et al. 2022; Gross et al. 2025). The mechanistic basis and therapeutic implications of this microglial senescence axis are discussed in detail in Section 5.2.

4. OLCs Interplay With Resident CNS Cells

4.1. OLCs' Relationship With Neurons in Health and MS

Physiological OPC‐neuron communication occurs via diverse receptor‐ligand signaling axes. Bergles and colleagues established that hippocampal pyramidal neurons form functional glutamatergic synapses onto OPCs both in vitro and in vivo, coupling neuronal activity to rapid OPC calcium signaling (Bergles et al. 2000).

OPC surface AMPA receptors mediate activity‐dependent synaptic plasticity that regulates OPC maturation (Bergles et al. 2000). In addition, OLs sense signal transduction activity of neurons by sensing neuron‐derived glutamate via NMDARs (Saab et al. 2016). NMDAR activation promotes GLUT1 surface expression, a glucose transport protein, and enhances glucose import into the OL cytoplasm where glucose is converted into lactate via glycolysis and then shuttled through monocarboxylate transporters (MCTs) found in the myelin sheath and axon (Saab et al. 2016; Lee et al. 2012). Moreover, BDNF release by OL participates in glutamate vesicle pool and glutamate release, indicating its synaptic transmission and plasticity (Jang et al. 2019) (Figure 2). OLs also release extracellular vesicles containing enzymes such as sirtuin 2 (SIRT2), a regulator of gluconeogenesis, that mediate neuronal metabolism (Chamberlain et al. 2021). Notably, OL‐derived extracellular vesicles (EVs), particularly exosomes originating from multivesicular bodies (MVBs), are increasingly recognized as key modulators of neuronal health. These lipid bilayer‐enclosed vesicles transport molecular cargoes such as proteins, lipids, nucleic acids, and metabolites, and are selectively enriched in non‐compact myelin areas and axonal loops (Fruhbeis et al. 2013; Hsu et al. 2010). Upon release, oligodendrocytic EVs are taken up by neurons, where they influence cellular functions and have been shown to enhance neuronal viability in vitro (Fruhbeis et al. 2020).

FIGURE 2.

Oligodendrocyte and neuron interaction in healthy condition mGluRs and CP‐AMPA expressed on the surface of OPC facilitate synaptic communication with neurons. The synaptic interactions between OPCs and neurons play an important role in neural circuit remodeling and the functional integration of OPCs. Mature OLs recognize neuronal signal transduction activity of neurons by sensing NMDARs. Additionally, BDNF derived from OLs regulates the glutamate vesicle pool and glutamate release, thereby contributing to synaptic transmission and plasticity. EVs from OLs are internalized by neurons, altering cellular processes and supporting neuronal viability.

Furthermore, optogenetic studies have shown that neuronal activity promotes OPC proliferation, oligodendrogenesis, and myelin remodeling (Gibson et al. 2014). This intimate interaction enables modulation of neuronal activity, density, circuitry, and metabolic needs, as well as OPC differentiation and active myelination at the basal physiological level. Intriguingly, recent data reported that activity‐driven myelin sheath growth requires mGlu5R signaling in vivo, strengthening a direct molecular link from neuronal activity to myelin remodeling (Braaker et al. 2025).

Neuronal activity engages the OLCs to generate new OLs and remodel myelin, an adaptive process that tunes conduction timing and circuit synchrony (Braaker et al. 2025). McKenzie et al. showed that blocking adult oligodendrogenesis prevents motor skill learning while baseline movement remains intact, directly linking activity to myelin remodeling and behavior (McKenzie et al. 2014). From a demyelination perspective including MS, meaningful recovery requires restoring neuron‐OL signaling and promoting OPC differentiation and new myelin rather than only stopping further myelin loss (McKenzie et al. 2014).

MS‐associated mitochondrial ROS overproduction disrupts OL glycolytic/lipogenic pathways essential for myelin biogenesis and maintenance. Eventually, these outcomes trigger axonal impairment (Lopez‐Muguruza and Matute 2023). These oxidative and metabolic insults disrupt the axon–OL metabolic coupling (e.g., GLUT1‐MCT‐dependent lactate support) and dampen activity‐dependent neuronal signaling to OPCs/OLs (AMPAR/NMDAR/mGluR5), thereby breaking the bidirectional neuron–OLC communication that underlies adaptive myelination (Lopez‐Muguruza and Matute 2023; Bergles et al. 2000; Braaker et al. 2025). Overall, delineating how synaptic inputs to OPCs, metabolic coupling via GLUT1‐MCTs, and EV‐mediated signaling converge on myelin remodeling may reveal actionable targets to enhance adaptive myelination. Such mechanism‐anchored interventions have the potential to promote remyelination and improve clinical outcomes in MS.

Therefore, a comprehensive understanding of OPC‐neuron interactions in demyelinating diseases is crucial for identifying therapeutic strategies that can be translated into meaningful benefits for patients.

4.2. OLCs Interplay With Astrocytes in Health and MS

4.2.1. Astrocytes Regulate OLC Development

Regarding OL development, including the sequential processes of OPC proliferation, differentiation, and OL maturation/myelination, the supportive role of astrocytes has been well‐established based on several studies (Table 1). Astrocyte‐derived PDGF functions as a potent mitogen for OPCs, promoting progenitor expansion while suppressing premature differentiation (Raff et al. 1988). Bogler et al. demonstrated that combined PDGF/bFGF signaling maintains OPC self‐renewal while blocking differentiation, establishing both as essential OPC mitogens (Bögler et al. 1990). Another key factor that stimulates OL differentiation and myelination enhancement is leukemia inhibitory factor‐like protein (LIF) in a conditioned medium secreted by astrocytes (Gard et al. 1995). Astrocyte‐derived LIF, released in response to electrical impulse activity in axons, was found to promote myelination by mature OLs (Ishibashi et al. 2006). In addition, ciliary neurotrophic factor (CNTF) has been suggested to be an essential factor for OL survival. Astrocytes stimulated by CNTF produce growth and trophic factors that promote OPC proliferation (Albrecht et al. 2007). Furthermore, recent studies have demonstrated that astrocytes stimulated with CNTF by neural stem cells (NSCs) upregulate the gene expression of cardiotrophin‐like cytokine 1 (Clcf1), thereby promoting OPC differentiation (Ji‐wei et al. 2022). Other examples of essential factors are BDNF, neuregulin‐1 (NR‐1), and neurotrophin‐3 (NT‐3) (Miyamoto et al. 2015; Schmid et al. 2003; Vondran et al. 2010; Cohen et al. 1996; Kumar et al. 2007; Zhu et al. 2012). Collectively, these findings underscore the multifaceted and indispensable role of astrocytes in orchestrating OLC progression—from the early stages of OPC proliferation to terminal differentiation and myelination—through a tightly regulated, cue‐dependent release of trophic and mitogenic factors.

TABLE 1.

Astrocyte‐derived factors in OLC development.

Soluble factors	Physiological highlights on OPCs or OLs	References
PDGF	Acts as a mitogen to promote division of the bipotential OPCs in neonatal rat optic nerve	(Raff et al. 1988)
FGF2	Acts as a regulator inhibiting differentiation of OPCs, but promoting extended self‐renewal in cooperation with PDGF	(Bögler et al. 1990)
BDNF	Astrocyte‐derived BDNF protects the OPC maturation from cerebral hypoperfusion in a TrkB‐dependent manner in vitro in OPCs/Astrocytes co‐cultures and in vivo in the transgenic mouse downregulated with astrocyte‐specific BDNF	(Gard et al. 1995; Miyamoto et al. 2015)
LIF or LIF‐like protein	Function as a paracrine regulator of OL survival and differentiation for maintaining a myelinogenic state	(Gard et al. 1995; Ishibashi et al. 2006)
	Promoting myelination in response to electrical impulse activity in axons mediated by astrocytic LIF
CNTF	Astrocytes activated by CNTF release neurotrophic factors that promote OPCs proliferation induce the Clcf1 gene in astrocyte, thereby promoting OPCs differentiation	(Albrecht et al. 2007; Ji‐wei et al. 2022)

4.2.2. Interactions of OLCs and Astrocytes in Regulating BBB Integrity and Function

Astrocyte end‐feet extensively envelop cerebral blood vessels, covering up to 90% of brain vasculature and serving as crucial points of interaction for transferring nutrients, metabolites, and ions from the bloodstream to the brain (Sweeney et al. 2018). Although astrocytes are recognized as a key contributor to maintaining BBB integrity, recent studies have revealed that OPCs also play a role in BBB integrity (Seo et al. 2014). OPCs enhance BBB integrity through the PDGF‐BB/PDGFRα pathway, and OLs can regulate BBB integrity (Kimura et al. 2020).

Additionally, TGF‐β from OPC‐cultured media activates the MEK/ERK signaling pathway, resulting in enhancing tight junction protein expression and thereby promoting BBB integrity (Seo et al. 2014). Moreover, it is reported that OPCs migrate to a certain position along with the intracephalic vascular system during CNS development, indicating that they may closely interact with astrocytes in vascular systems (Tsai et al. 2016). Evidence showing direct interaction between OLCs and astrocytes affecting neurovascular units is still lacking. However, the most recent study demonstrated that astrocytic lipocalin‐2 (LCN2) crosstalk with OLs through lipoprotein receptor‐related protein 2 (LRP2), which subsequently activates the JNK3 pathway, resulting in secondary demyelination and worsening post‐ischemic stroke (Huang et al. 2025). Given that BBB dysfunction is a key feature of ischemic stroke, regulating the crosstalk between astrocytes and OLs through LCN2‐LRP2 in terms of BBB integrity may be a novel therapeutic strategy in properly maintaining homeostatic status.

4.2.3. OLCs Interaction With Astrocytes: Gap Junction Communication

OLs are connected to astrocytes via gap junctions, in which they communicate with connexin (Cx) to maintain myelin homeostasis, allowing the free flow of ions and metabolites (Domingues et al. 2016; Lutz et al. 2009). OLs express Cx32 and Cx47. In contrast, astrocytes express two types of connexins, Cx30 and/or Cx43, which form homotypic channels (Cx30:Cx30 or Cx43:Cx43) or heterotypic channels (Cx30:Cx43) to connect with each other. OLs communicate with adjacent astrocytes through heterotypic gap junctions composed of Cx43:Cx47 or, to a smaller degree, Cx30:Cx32 (Nagy et al. 2003; Orthmann‐Murphy et al. 2008). Disrupting the gap junctions coupling OLs and astrocytes results in delayed myelination, indicating that this physiological interaction is crucial for maintaining the maturation of OLs (Tress et al. 2012).

In MS, clusters of OPCs play a role in causing changes in vascular permeability by affecting the astrocyte foot processes. They showed that OPCs require a vascular scaffold to migrate and repopulate demyelinated regions. However, the failure of proper detachment from the vasculature leads to a disruption of BBB integrity (Niu et al. 2019). In addition, the reduction of certain types of connexins, such as Cx32 and Cx47 in OLs, diminishes the OLs‐OLs or OLs‐astrocytes interactions, a phenotype observed in active and chronic lesions of MS. Furthermore, the absence of the connexins in OLs can aggravate clinical EAE, leading to increased myelin loss in mice (Papaneophytou et al. 2018). Moreover, the astrocytic connexin, Cx43 loss was found in remyelinating and chronically active lesions in MS (Masaki 2015). These observations support a mechanistic axis in which connexin‐defined glial coupling to vascular stability, rather than representing a parallel and independent pathology. Future studies should: (i) quantify spatiotemporal dynamics of Cx43:Cx47 and Cx30:Cx32 assemblies in vivo during lesion initiation, progression, and remyelination; (ii) test causality by cell type–specific restoration or stabilization of astrocyte–OL gap junctions (e.g., using conditional knock‐in, inducible rescue, or peptide mimetics) and assess effects on BBB permeability and myelin repair; and (iii) modulate OPC–vascular adhesion and astrocytic end‐foot scaffolds in combination with connexin reinforcement to define synergistic control points. These approaches will establish whether targeted preservation of glial gap junctions is sufficient to maintain BBB integrity and limit lesion expansion.

4.2.4. Interaction of OLCs With Astrocytes in MS

Crosstalk between OLCs and astrocytes plays a vital role in maintaining CNS development, homeostasis, and adapting to demyelinating conditions including MS. This is a complex process involving various receptors on OLCs and stimuli from astrocytes, and vice versa (Table 2).

TABLE 2.

Reactive astrocytic functions and their associated factors.

Reactive astrocytic function	Factor	References
Chemoattractant; recruitment of immune cells into the lesion of MS	CCL2, CCL3, CCL4, CCL5, CCL20, CXCL10, CXCL12	(Brambilla et al. 2014; Ambrosini et al. 2005)
Boosting proinflammatory responses and Tc and Th cell recruitment	CXCL12, IL‐6, IL‐12, IL‐23, IL‐17	(Calderon et al. 2006; Correale and Farez 2015)
Nuclear translocation of NF‐κB in astrocytes; regulation of neuroinflammation	TNF‐α, IL‐1β, IL‐6, ROS	(Brambilla et al. 2009; Lawrence et al. 2023)
Anti‐inflammatory effects	IL‐4, IL‐10, TGF‐β1	(Zhang et al. 2024; Vermersch et al. 2022; Brambilla 2019)
Improvement of remyelination	CXCL12, IL‐11	(Calderon et al. 2006; Zhang, Taveggia, et al. 2006; Patel et al. 2012; Szpakowski et al. 2022)
Inhibition of remyelination	CXCL1, CXCL10, CXCL12, MMP9, MMP12	(Brambilla 2019; Gorter and Baron 2020)
BBB disruption	IL‐1β, MMP9, VEGF, NO	(Spencer et al. 2018; Argaw et al. 2006)

Astrocytes are the key cell type synthesizing cholesterol in the CNS (Wong et al. 2007), which plays crucial roles in constituting myelin in OLs (Saher et al. 2005). Thus, loss of cholesterol secretion from reactive astrocytes leads to demyelination and would limit remyelination in MS (Itoh et al. 2018). According to the recent study regarding astrocyte‐OL interaction, astrocytes undergo a reactive process during remyelination, showing the increase of GFAP⁺ and the proportion of total astrocytes (SOX9⁺) cells when compared to vehicle and control groups in the model of demyelination induced by myelin toxin lysolecithin in mice (Molina‐Gonzalez et al. 2023). The nuclear factor erythroid‐2‐related factor 2 (Nrf2) pathway, known for its neuroprotective role in astrocytes during myelin damage, was upregulated during the demyelination phase. However, the expression of Nrf2 subsequently decreased during remyelination. They also demonstrated that Nrf2 activation in astrocytes affects the decrease of the cholesterol pathway, resulting in OL death and aggravating demyelination (Molina‐Gonzalez et al. 2023). However, treatment of luteolin, a flavonoid suppressing Nrf2 hyperactivation, restores the number of OLCs, mature OLs, and remyelination by downregulating the Nrf2 pathway (Molina‐Gonzalez et al. 2023). Taken together, these findings suggest that, in the context of astrocyte‐OL interaction, combinatorial therapeutic approaches targeting both the Nrf2 pathway and cholesterol biosynthesis for mature OLs' survival by astrocytic support could be a novel therapeutic strategy to boost remyelination in myelin damages (Figure 3).

FIGURE 3.

Interaction between OLCs and CNS cells in multiple sclerosis. Under healthy conditions, CNS‐resident microglia, astrocytes, neurons, and OLCs cooperate together to maintain homeostatic balance. However, in pathological conditions, the normal expression of BDNF and FGF is disrupted, potentially impairing OPCs' proliferation. Microglia and astrocytes release pro‐inflammatory cytokines, such as IL‐1β and TNF‐α, resulting in neuroinflammation and demyelination. Additionally, excessive glutamate release from neurons can induce OL damage, further exacerbating myelination deficits, as observed in MS.

In addition, it was reported that, under demyelinating conditions, astrocytes can be reprogrammed into OLCs via Sox2 overexpression, resulting in OPC maturation and remyelination (Farhangi et al. 2019). This suggests that during demyelination, astrocytes could shift roles from simply contributing to inflammation to actively participating in CNS repair by providing a cellular source for remyelination. Therefore, future studies investigating astrocytic Sox2 in compensating OLs' loss and promoting remyelination are needed to address the knowledge gap in terms of OL‐astrocytes interactions.

5. OLCs Interplay With Microglia in Health and MS

5.1. Microglia Regulate Oligodendrocyte Development

Microglia, CNS‐resident macrophages comprising 10%–20% of glial, orchestrate developmental phagocytosis, antigen presentation, and cytokine signaling critical for circuit maturation and homeostasis (Li and Barres 2018; Benveniste 1997; Colonna and Butovsky 2017). The most characterized function of microglia is that they rapidly and dynamically change their functional phenotypes from resting to activated in response to pathological conditions (Park et al. 2021; Davalos et al. 2005). Recent data has shown that not only are microglia involved in neuroinflammation, but they also contribute to supporting the establishment of neuronal circuits, as well as OPCs and OLs during development (Wlodarczyk et al. 2017; Hagemeyer et al. 2017; Wake et al. 2013).

Pang et al. highlighted that microglia‐conditioned medium protects OPCs from apoptosis due to growth factor withdrawal, resulting in promoting their differentiation. In addition, it has been reported that VEGF and insulin‐like growth factor (IGF)‐1 by microglia enhance OPCs differentiation (Pang et al. 2013). Similar to astrocytes, trophic factors secreted by microglia contribute to supporting OL lineage development (Santos and Fields 2021) (Table 3). For example, microglia switch from pro‐inflammatory to anti‐inflammatory when remyelination starts and secrete activin‐A, a dimeric glycoprotein, a key factor in enhancing OLs differentiation in ex vivo culture (Miron et al. 2013). The fidelity of this pro‐remyelinating microglial transition is itself age‐dependent; scRNA‐seq of remyelinating lesions using the lysolecithin model has demonstrated that the sequential microglial state transitions required for efficient repair—including the emergence of a myelin transcript‐enriched resolved state—are temporally delayed in aged animals, thereby providing a cellular basis for the well‐documented decline of remyelination capacity with age (Zia et al. 2025).

TABLE 3.

Microglia‐derived factors in OLC development.

Types	Factors	Microglia function	Beneficial or detrimental	References
Complement	C1q	OPCs differentiation	Detrimental	(Gao et al. 2022)
Receptor/Ligand	CX3CR1/CX3CL1	Myelin debris removal	Beneficial	(de Almeida et al. 2023)
		OPCs differentiation
Receptor	TREM2	Myelin debris removal	Beneficial	(Cignarella et al. 2020)
Cytokine	TNF‐α	Oligodendrogenesis	Beneficial	(Shigemoto‐Mogami et al. 2014)
		OPCs/OLs viability	Detrimental
Growth factor	VEGF	OPCs migration	Beneficial
Growth factor	BDNF	OPCs differentiation	Beneficial	(Miyamoto et al. 2015; Raffaele et al. 2025)
		OLs maturation
Growth factor	IGF‐1	OPCs differentiation	Beneficial	(Pang et al. 2013)
		OLs maturation
Chemical element	Iron	OLs viability	Beneficial	(Zhang, Surguladze, et al. 2006; Li et al. 2013)
		OLs maturation
Cytokine	TGF‐β	OPCs migration OPCs remyelination	Beneficial	(Lalive et al. 2005)
Receptor	Neurophilin‐1	OPCs migration	Beneficial
Cytokine	IL‐4	OPCs differentiation	Beneficial	(Butovsky et al. 2006)
		OPCs maturation
Cytokine	IL‐6	OPCs differentiation	Detrimental
		OPCs maturation
Cytokine	IL‐10	OPCs differentiation	Beneficial	(Miron et al. 2013)
		OPCs maturation
Cytokine	IL‐12	OPCs differentiation OPCs maturation	Beneficial	(Chung et al. 2022)
Growth factor	Activin‐A	OPCs differentiation	Beneficial	(Miron et al. 2013)
		OPCs maturation
Aerobic metabolites	ROS	OPCs/OLs viability	Detrimental	(Jana and Pahan 2007)
Enzyme	iNOS	OLs viability	Detrimental	(Pang et al. 2003; Jana and Pahan 2013)
		OLs maturation
Enzyme	MMPs	OPCs/OLs viability	Detrimental	(Hansmann et al. 2012; Diaz‐Sanchez et al. 2006)
Neurotransmitter	Glutamate	OLs viability	Detrimental	(Takahashi et al. 2003)
Cytokine	IFN‐γ	OLs viability	Detrimental	(Pouly et al. 2000; Chew et al. 2005)
		OPCs differentiation
Cytokine	IL‐1β	OLs viability	Detrimental	(Takahashi et al. 2003)
Cytokine	TGF‐β	OPCs differentiation	Detrimental	(Baror et al. 2019)
		OPCs maturation
Chemokine	CXCL1	OPCs migration	Detrimental	(Vora et al. 2012)

Recently, it has been reported that a microglia subpopulation in which clec7a, Igf1, Spp1, and gals genes are upregulated populates white matter regions (corpus callosum and cerebellum) and has an essential role in OPC maintenance, maturation, and myelination (Barclay et al. 2024). Liu et al. show that selective deletion of NG2⁺ glia, also known as OPCs, by using small molecule inhibitors of PDGF signaling pathways aggravates the homeostatic microglial profiles without influencing disease‐associated microglia profiles, suggesting that OPCs are vital to maintaining the microglia cellular state under physiological conditions (Liu and Aguzzi 2020). Given that microglia affect the process of OL development, and likewise, OPCs contribute to upholding microglial homeostasis, the interplay between microglia and OLs appears to be reciprocally bidirectional.

5.2. Pathological Relationship With Microglia in OL Demyelination and Remyelination in MS

The interplay between microglia and OPCs/OLs could have significant implications in the context of MS (Pons and Rivest 2020; Rahimian et al. 2022). Microglia regulate OPC migration, proliferation, and differentiation through cytokine and chemokine signaling under normal development (Santos and Fields 2021) as well as demyelinating diseases such as MS (Kalafatakis and Karagogeos 2021). The emerging evidence suggests that OLs produce immune mediators, such as CCL2, CCL3, and CXCL10, in response to IFN‐γ, possibly communicating with adjacent microglia and regulating their activation state (Balabanov et al. 2007). Moreover, αB‐crystallin, secreted from OLCs, has been identified as an anti‐inflammatory mediator (Ousman et al. 2007). Evidence suggests that the release of Activin A in microglia supports remyelination (Barclay et al. 2024). Another key analysis regarding OLs‐microglia crosstalk revealed the ligand–receptor interactions that shape their communication in MS. Microglia‐derived osteopontin (SPP1) engages with integrin receptors and CD44, which are known to express OLCs and may obstruct or support remyelination in MS (Yim et al. 2022; Back et al. 2005; Qiu et al. 2023). These signals may influence cell survival pathways, including those supporting autoreactive T cells (Hur et al. 2007). Similarly, microglia‐derived neuropilin‐1 induces developmental OPC proliferation and OPC expansion and repair after demyelination (Sherafat et al. 2021). Together, these data suggest that reciprocal OL‐microglia communication through cytokine and the ligand–receptor interactions not only shapes inflammatory tone and myelination dynamics but also positions OLCs as active immunomodulatory players rather than passive targets in MS lesions. Moreover, as mentioned above, recent scRNA‐seq and snRNA‐seq studies have revealed that disease‐associated OLs in human MS lesions are highly heterogeneous and consist of multiple subpopulations rather than a single reactive state (Pandey et al. 2022). Falcão et al. first established in human MS tissue that disease‐specific OLC subpopulations—termed immunoresponsive OLs—arise selectively in the MS CNS environment and are not present in healthy controls, providing the foundational evidence that the inflammatory milieu actively instructs a distinct OLC identity (Falcao et al. 2018). Building on this, Pandey et al. demonstrated that these disease‐associated OLC states are defined by at least three transcriptional modules: IFN‐responsive OLs expressing Stat1, Irf7, Ifit1, and H2‐D1; immune‐associated OLs enriched for C4b, Serpina3n, and Anxa2; survival‐associated OLs expressing Cdkn1a, Bax, and Ddit3 (Pandey et al. 2022). As mentioned above, this multi‐disease analysis further revealed that these OLC transcriptional programs are shared across MS, ALS, and AD, indicating a conserved OLC stress‐response architecture that is activated regardless of the primary disease trigger (Kenigsbuch et al. 2022; Pandey et al. 2022). Importantly, several of these immune‐reactive OLC states exhibit transcriptional programs associated with MHC signaling, IFN responses, and immunoproteasome activation, suggesting that chronic inflammatory environments actively reprogram OLC identity within MS lesions rather than merely impairing remyelination passively (Pandey et al. 2022). Consistent with this, CD8⁺ T cells have been directly shown to induce IFN‐responsive OLC and microglial states in white matter, with Rag1‐deficient mice lacking lymphocytes showing marked reductions in these activated glial populations (Kaya et al. 2022), providing a mechanistic link between adaptive immune infiltration and the emergence of disease‐associated OLC states within inflamed white matter. These transitional states spatially and molecularly overlap with activated microglial niches, supporting the concept that microglia‐derived inflammatory signaling critically shapes disease‐associated OLC remodeling in chronic demyelinating lesions (Pandey et al. 2022). Critically, a landmark single‐cell spatial transcriptomic study directly mapped the cellular architecture sustaining this inflammatory microglial‐OLC crosstalk at the rim of chronic active MS lesions (Feng et al. 2025). Feng et al. combined snRNA‐seq with MERFISH to generate a high‐resolution spatial atlas of chronic active lesion (CAL) tissue, identifying a pathogenic niche in which CD8⁺ T cells co‐localize with inflamed microglia displaying a heightened IFN response together with dysregulated lipid metabolism (Feng et al. 2025). These lesion rim microglia, designated as microglia inflamed in MS (MIMS), exhibited impaired ABCA1/G1‐mediated cholesterol efflux, driving intracellular lipid accumulation and a foam cell phenotype that amplified local inflammatory signaling, which further impairs their lipid metabolism and phagocytic capacity, creating a self‐reinforcing cycle of metabolic dysfunction and remyelination suppression (Feng et al. 2025). Mechanistic validation in EAE demonstrated that conditional deletion of ABCA1/G1 in microglia exacerbated foam cell formation and inflammatory demyelination, while pharmacological targeting of sterol metabolism reduced both pathologies (Feng et al. 2025). Importantly, the IFN‐responsive OLC states enriched within this niche are identified by single‐cell spatial transcriptomic profiling of chronic active MS lesions (Feng et al. 2025), providing direct spatial and mechanistic evidence that CD8⁺ T cell‐instructed, lipid‐dysfunctional microglia actively sustain repair‐incompetent OLC states within CAL rims (Feng et al. 2025). These findings identify the aberrant microglial lipid metabolism‐IFN axis as a therapeutically actionable mechanism perpetuating OLC injury and remyelination failure in chronic progressive MS (Feng et al. 2025). Beyond the spatially organized inflammatory niche defined by Feng et al. (Feng et al. 2025), converging evidence now implicates microglial senescence as a distinct and therapeutically tractable mechanism through which microglia impair OLC repair in chronic MS. Gross et al. demonstrated that senescence‐associated (including p16) microglia accumulate within demyelinated lesions and persist with advancing age, secreting a SASP that includes CCL11/Eotaxin‐1 as a potent inhibitor of OLC maturation (Gross et al. 2025). Senolytic elimination of these cells enhanced remyelination in young and middle‐aged mice, while CCL11 inhibition partially recapitulated this effect, supporting a direct SASP–OLC axis of repair suppression (Gross et al. 2025). Extending these findings to human disease, Fagiani et al. applied single‐cell and spatial transcriptomics to post‐mortem MS brain tissue and patient‐derived hiPSC neural organoids, finding that senescent‐like glial cells—with microglia being the most vulnerable cell type—accumulate preferentially in CAL, with senescence‐like transcriptomic signatures forming spatial gradients from the lesion core outward into periplaque white matter (Fagiani et al. 2025). Critically, inflammation‐induced microglial senescence in patient‐derived organoids could be partially reversed by CNS‐penetrant anti‐inflammatory treatment, and patient MRI data confirmed that higher CAL burden correlates with accelerated brain aging (Fagiani et al. 2025). Collectively, these studies reveal that senescent microglia operating through the SASP represent a mechanism of remyelination suppression that is distinct from—yet spatially overlapping with—the acute CD8⁺ T cell‐driven inflammatory niche, and that both axes must be considered when designing therapies to restore OLC repair capacity in progressive MS (Gross et al. 2025; Feng et al. 2025; Fagiani et al. 2025).

Beyond their well‐established pro‐inflammatory functions during demyelination, accumulating evidence suggests that distinct subsets of microglia and monocyte‐derived macrophages also exert essential reparative functions during remyelination (Miron et al. 2013). Early studies demonstrated that a transition from pro‐inflammatory to pro‐regenerative microglia/macrophage states occurs at the initiation of remyelination, and that these reparative phenotypes promote OL differentiation through factors such as activin‐A (Miron et al. 2013). Selective depletion of repair‐associated microglia/macrophages using mannosylated clodronate liposomes (MCLs) impaired OL differentiation and delayed remyelination, highlighting the functional importance of these cells during myelin repair (Miron et al. 2013).

Recent single‐cell transcriptomic studies further expanded this concept by identifying disease‐associated microglia (DAM) state enriched in demyelinating lesions and white matter injury models (Barclay et al. 2024). These DAM populations exhibit context‐dependent plasticity and express genes associated with phagocytosis, myelin clearance, and tissue repair, including Clec7a, Apoe, Ctsb, and CD63 (Barclay et al. 2024). Importantly, experimental depletion of DAM populations using Clec7a‐CreERT2 impaired efficient remyelination following cuprizone (CPZ)‐induced demyelination, supporting a protective role of specific microglia/macrophage states during myelin repair (Barclay et al. 2024).

In parallel, emerging evidence suggests that infiltrating monocyte‐derived macrophages (MoDM) can acquire repair‐associated phenotypes characterized by enhanced lipid metabolism, phagocytosis, angiogenic activity, and pro‐remyelinating properties (Zhang et al. 2025). In a recent tMCAO‐induced ischemic stroke model, a subset of CCR2+ monocyte‐derived repair‐associated macrophages (RAMf) expressing high levels of GPNMB and CD63 promoted oligodendrogenesis, OPC proliferation, white matter repair, and remyelination following injury (Zhang et al. 2025). Mechanistically, these cells exhibited enhanced lipid recycling and myelin debris clearance capacities, which are considered essential processes for efficient remyelination. Moreover, transplantation of RaMf improved white matter integrity and increased newly generated OLs in the injured brain (Zhang et al. 2025). These findings suggest that infiltrating MoDM may exhibit functional heterogeneity and can adopt reparative phenotypes that support OLC regeneration and remyelination under specific pathological conditions.

Collectively, these findings suggest that microglia and MoDM exhibit substantial functional heterogeneity during CNS demyelinating diseases. Rather than acting solely as mediators of inflammatory injury, specific immune states of these cells may actively coordinate OPC differentiation, lipid metabolism, myelin debris clearance, and regenerative remodeling within demyelinated lesions. Therefore, modulating reparative microglial/macrophage states may represent a promising therapeutic strategy to enhance remyelination and functional recovery in MS.

In addition, a recent transcriptomic study revealed that OPCs and microglia are closely related to myelin and lipid metabolism in the CPZ‐induced demyelination and remyelination mice model. Interestingly, crosstalk analysis identified 43 receptors (e.g., CSF1R, IGF1R, and JAM3) and 115 target genes (e.g., Bbc3, Gadd45b and Hist1h3d) in OPCs, while 47 corresponding ligands (e.g., TNF, SPP1, Serpine1, and CSF1) were found in microglia (Enrich‐Bengoa et al. 2022). This genetic crosstalk regulates its target gene expression associated with immune response and OPC proliferation and differentiation, resulting in modulating de‐ and remyelination in time‐dependent manners (Enrich‐Bengoa et al. 2022). This suggests that viewing OLs as immunomodulatory cells that interact with other immune cells, such as microglia, may open new avenues for therapeutic strategies in MS (Figure 3).

Notably, recent high‐resolution spatial transcriptomic profiling via in situ sequencing has demonstrated that disease‐associated glia states including microglial and oligodendroglia populations, are widely and dynamically induced across the CNS parenchyma regardless of focal demyelinating lesion areas during during EAE lesion development (Kukanja et al., 2024). This spatiotemporal approach indicates that widespread microglial activation and glial state shifts can precede or occur independently of focal demyelinating lesions (Kukanja et al., 2024), indicating that the induction of disease‐associated glia states is closely linked to the formation of focal lesions, but it can occur independently. Another study has proved that both microglia and OPC act as the early responder and undergo concurrent proliferation during the early stage of lesion development in EAE through MRI‐guided spatiotemporal RNA profiling in marmoset brain mapping (Lin et al., 2025). These cells construct concentric glial barrier at the lesion periphery, prior to their eventual replacement by blood‐derived monocytes and lymphocytes during lesion progression (Lin et al., 2025), providing their important early role in shaping MS‐like pathology.

6. OLCs Interplay With Peripheral Immune Cells in Health and MS

6.1. Disrupted CNS Barrier and Interactions of OLCs and T Cells

The CNS maintains immune privilege through three major barriers: the BBB, blood‐leptomeningeal, and choroid plexus barriers, which collectively restrict physiological leukocyte entry into the parenchyma (Muldoon et al. 2013). In MS and other CNS pathologies, these barriers are compromised, permitting dramatically increased T cell infiltration into lesions. Three major CNS barriers involving T cell infiltration have been identified. First, the BBB is the primary entrance into CNS parenchyma (Angelini et al. 2023). Second, the blood‐leptomeningeal barrier (BLMB) is permissive to the passage of molecules and cells present in blood. Although tight junctions connect the endothelial cells in the leptomeninges, preventing the infiltration of peripheral immune cells, dural vessels are relatively devoid of tight junctions found in the brain or leptomeningeal blood vessels. Thus, this system makes them capable of allowing access of T cells to the subpial CNS region and cerebrospinal fluid (CSF) (Alves de Lima et al. 2020; Aydin et al. 2023). Lastly, the choroid plexus serves as the primary connection that links the peripheral blood to the CSF (Verhaege et al. 2026). T cells traverse these barriers via cell adhesion molecules such as integrins, selectins, and chemokine receptors (Timmerman et al. 2016). Endothelial chemokines further facilitate T cell migration by engaging their cognate receptors across BBB and blood‐CSF barriers in autoimmune diseases (Heng et al. 2022).

Infiltrating T cells via the damaged CNS barriers are involved in OLCs demyelination and remyelination in MS patients or animal models (Larochelle et al. 2021). For instance, T helper 17 (Th17) cells can compromise the BBB via binding to IL‐17 and IL‐22 receptors on brain endothelium and induce additional recruitment of CD4⁺ lymphocytes, leading to neuronal death in EAE (Kebir et al. 2007). In particular, infiltrating CD4⁺ Th17 cells were found to be in long‐term direct contact with OLs and CD4⁺ Th17 cell‐derived secreted glutamate impaired myelination and processes of OLs in acute EAE (Larochelle et al. 2021). Upon direct contact with T cells, OLs change their transcriptional profile involving cell death and inflammation (Jamann et al. 2024). Among altered transcriptome, activated leukocyte cell adhesion molecule (ALCAM/CD166) on mature OLs interacted with CD6 on the surface of Th17 cells, which mediates Th17 injury and confers a harmful effect on OLs; however, knockdown of ALCAM in OLs reduced their injury induced by Th17 cells (Jamann et al. 2024). Recent studies have identified that high‐mobility group box 1 (HMGB1) secreted by OPCs triggers infiltration of pathogenic T cells by disrupting the BBB, thereby leading to migration of CD4⁺ T cells in EAE‐induced mice; OPC‐specific HMGB1 knockout mice show reduced levels of BBB breakdown and infiltrated immune cells including CD4⁺ T cells (Kim et al. 2025). These findings demonstrate a modulatory role of OPC‐derived HMGB1 in regulating BBB integrity and CD4⁺ T cell infiltration in the EAE context; whether this mechanism operates equivalently in human MS remains to be directly established.

In addition, in patients with MS, oligoclonal expansion of CD8⁺ T cells was found in brain parenchyma and CSF, indicating the infiltration of CD8⁺ T cells mainly present in the periphery (Galea et al. 2007). Enhanced accumulation of CD8⁺ T cells is detected around the BBB, which are involved in brain endothelial cell death and BBB breakdown in MS (Aydin et al. 2023). These CD8⁺ T cells seem to participate in OLs' loss (Kaya et al. 2022). Through these previous results, infiltrated peripheral T cells, such as CD4⁺ and CD8⁺ T cells, interact with OLs through direct contact, ultimately leading to OL injury and death via disrupted CNS barrier.

Beyond serving as targets of infiltrating lymphocytes, OPCs can actively shape neuroinflammation through low‐density lipoprotein receptor‐related protein 1 (LRP1)‐dependent antigen cross‐presentation (Fernandez‐Castaneda et al. 2020). LRP1, a member of the LDL receptor family that is involved in receptor‐mediated endocytosis and intracellular signaling, is expressed throughout the OLCs and functions as a phagocytic receptor involved in myelin debris clearance (Fernandez‐Castaneda et al. 2020). In addition, LRP1 plays a critical role in inflammatory regulation through modulation of cytokine production (Mantuano et al. 2016; Yang et al. 2016). In oligodendroglia‐specific Lrp1 knockout mice, normal myelin development was preserved, indicating that LRP1 is dispensable for OPC differentiation into mature OLs; however, these mice exhibited markedly better outcomes in both EAE and CPZ, accompanied by a robust dampening of inflammation (Fernandez‐Castaneda et al. 2020). Mechanistically, LRP1‐deficient OPCs displayed impaired antigen cross‐presentation machinery, suggesting a failure to propagate the inflammatory response and thereby promoting faster myelin repair and neuroprotection (Fernandez‐Castaneda et al. 2020). These findings place OPCs as active regulators of neuroinflammation rather than passive bystanders and provide a mechanistic bridge from barrier‐driven T cell infiltration to the helper T cell‐OLC crosstalk discussed in the following section (Figure 4).

FIGURE 4.

Interaction between OLCs and infiltrating peripheral immune cells Under healthy conditions, CNS barriers, such as BBB and BCSFB, protect the CNS parenchyma by separating it from bloodstream and selectively regulating the entry of peripheral substance into the CNS. However, in pathological conditions such as MS, peripheral immune cells breach this CNS barriers and invade into the CNS tissues by compromising their structural integrity. Peripheral immune cells, including CD4⁺ Th1 cells, CD4⁺ Th17 cells, CD8⁺ Tc cells, B cell and monocytes contribute to disturbance of immune system in the CNS. Secreted inflammatory mediators play a pivotal role in determining the severity of MS symptoms. For instance, IFN‐γ induced by CD4⁺ Th17 cells can contribute to OL death and inhibits the differentiation of OPCs. Similarly, IL‐17 derived from CD4⁺ Th17 cells impairs OL and OPCs differentiation. Furthermore CD8⁺ Tc cell‐induced glutamate exacerbates OLs damage, underscoring the critical role of balanced interactions between peripheral immune cells and OLCs in maintaining CNS homeostasis.

6.2. CD4 ⁺ Helper T Cells and OLCs in MS

MS initiation occurs through peripheral activation of CNS antigen‐specific CD4 T helper (Th) cells (Goverman 2009). Following antigen recognition, CD4⁺ Th cells differentiate into effector subsets—Th1 or Th17—producing distinct inflammatory cytokines. These cytokines activate neighboring glia and recruit additional inflammatory cells into the CNS.

Th1 cells secrete TNF‐α, IFN‐γ, and IL‐2 with CSF IFN‐γ levels correlating closely with MS severity (Goverman 2009). TNF‐α derived from CD4⁺ T cells exerts direct cytotoxic effects on OLs and suppresses OPC differentiation by impairing mitochondrial function (Renno et al. 1995; Bonora et al. 2014). In addition, TNF‐α inhibition prevents OL apoptosis and enhances OPC differentiation in EAE (Valentin‐Torres et al. 2018). Similarly, IFN‐γ upregulates Fas expression, triggering OL apoptosis (Pouly et al. 2000), while also directly inhibiting OPC differentiation (Chew et al. 2005). IL‐2 from T cells inhibits OPC proliferation and treatment of recombinant human IL‐2 demonstrates OL cytotoxicity (Saneto et al. 1986; Curatolo et al. 1997).

Th17 cells produce IL‐17A/F, IL‐22, GM‐CSF, IL‐21, and IL‐6, driving CNS inflammation (Maddur et al. 2012; Leung et al. 2010; Korn et al. 2009). Among inflammatory cytokines, IL‐17, abundantly expressed in MS and EAE (Komiyama et al. 2006), upregulates K⁺ Channels (Kv1.3) (Liu et al. 2021) and NOTCH1‐NF‐κB signaling in OPCs, impairing proliferation, differentiation, and remyelination (Wang et al. 2017). Although the expression of IFN‐γ in Th17 cells was lower than that in Th1 cells, Th17 cells also produce both IL‐17 and IFN‐γ in response to IL‐23 in Th 17 cell lines, derived from MS patient tissue (Kebir et al. 2009). In parallel, the presence of Th17 cells expressing both IL‐17 and IFN‐γ was observed in higher levels in MS brain tissue, suggesting a potential role for these double‐positive effector cells in the disease process (Kebir et al. 2009). Also, IL‐22 increases NF‐κB signaling and Fas expression in OLs, thereby leading to apoptotic cell death of OLs (Zhen et al. 2017). Paradoxically, in CPZ‐induced demyelination model, IL‐22 treatment increased the level of MBP in the corpus callosum, indicating enhanced myelination (Zamali et al. 2024). Collectively, these results indicate that CD4+ T cells play a central role in both demyelination and remyelination in MS.

In addition to being targets of infiltrating lymphocytes, OLCs themselves acquire disease‐associated immune functions in MS and EAE. Single‐cell transcriptomic analyses of OLCs isolated from EAE spinal cord and human MS brains revealed that distinct disease‐associated OLCs upregulated genes associated with antigen‐processing and presentation pathways, including MHC class I and II programs, including Stat1, B2m, H2‐K1, H2‐D1, Tap1, Psmb9, H2‐aa, H2‐ab1, and Cd74, together with immunoregulatory genes such as Serpina3n, Igtp, Nlrc5, and Serping1 (Falcao et al. 2018). Although OLs had traditionally not been considered to express MHC class II in MS (Lee and Raine 1989), this disease‐associated transcriptional state includes IFN‐γ‐responsive genes such as Ifih1, Iigp1, Trim34, Irf7, Irgm1, Irgm2, Igtp, and Zbp1, suggesting that inflammatory cues can confer antigen‐presenting capacity on OLCs within the CNS lesion (Falcao et al. 2018). These findings further support the concept that chronic inflammatory environments actively reprogram OLCs into immune‐reactive states capable of interacting with infiltrating T cells within demyelinating lesions. Functionally, the key consequence of this shift is that IFN‐γ‐pretreated OPCs loaded with MOG35‐55 peptide activate MOG‐specific CD4⁺ T cells, leading to increased IFN‐γ and TNF production, whereas naïve T cells remain largely unresponsive under the same conditions (Falcao et al. 2018). Together, these findings support a model in which IFN‐γ‐driven MHC class II induction enables OPCs to reactivate antigen‐experienced CD4⁺ T cells locally, positioning OLCs as conditional antigen‐presenting cells that can amplify lesion‐associated T cell responses (Falcao et al. 2018). Equally important, OLCs are not merely targets of helper T cell‐derived cytokines; they also acquire the ability to regulate CD4⁺ T cell responses themselves.

6.3. CD8 ⁺ Cytotoxic T Cells and OLCs in MS

CD8⁺ cytotoxic T cells are essential in OLC biology and the progression of MS. CD8⁺ T cells are one of the most predominant T cell populations found in CNS lesions of MS patients (Wagner et al. 2020). Clonal expansion occurs more frequently in CD8⁺ T cells than in CD4⁺ T cells in the brain, CSF, and blood of MS patients (Skulina et al. 2004; Babbe et al. 2000). In EAE, myelin‐specific CD8⁺ T cells are responsible for critical autoimmune responses as potential contributors to autoimmune damage (Huseby et al. 2001). During CNS inflammatory response, CD8⁺ T cells exert an inhibitory effect on OPC proliferation via secretion of cytokines, including IFN‐γ (Kirby et al. 2019). CD8⁺ T cells can impair OLs by releasing glutamate, resulting in neuronal cell death (Melzer et al. 2013). The OLs‐specific CD8⁺ T cells overproduced cytotoxic IFN‐γ and granzyme B, and induced apoptotic cell death in OLs and demyelination, accompanied by axonal damage in MS‐like lesions (Saxena et al. 2008). Infiltrating MBP‐specific CD8⁺ T cells induced monocyte‐ and monocyte‐derived cell‐driven ROS overproduction, regarded as contributors to aggravate disease (Wagner et al. 2020). Conversely, OLCs can also regulate CD8⁺ T cells (Fonta et al. 2025). A recent study using a CD8⁺ T cell‐driven MOG‐GP mouse model of chronic CNS autoimmunity has demonstrated that Olig2⁺ OLCs dominantly express IL‐33, which aggravates tissue injury of the inflamed lesions and disease severity in CNS autoimmune disease (Fonta et al. 2025). In particular, OL‐derived IL‐33 elicits the persistence and differentiation of autoreactive CD8⁺ T cells via direct contact with ST2 receptor, driving transcriptional reprogramming of CD8⁺ T cells and activating microglia; conditional IL‐33 knockout in OLs reduced infiltrating CD8⁺ T cell infiltration and suppressed pathogenicity in this animal model (Fonta et al. 2025). It should be noted that these findings are derived from a transgenic mouse model rather than from human MS tissue, and whether OLC‐derived IL‐33 drives equivalent CD8+ T cell responses in human MS tissue has not yet been directly demonstrated. Further work in human MS tissue and patient‐derived systems is needed to establish the translational relevance of this axis.

Notably, recent single‐cell RNA sequencing further demonstrated that CD8⁺ T cells can induce IFN‐responsive OL states within inflammatory white matter regions (Kaya et al. 2022). IFN‐responsive OLs upregulated genes including Stat1, Ifi27l2a, H2‐D1, and H2‐K1, indicating activation of inflammatory and antigen‐processing programs. These OLs spatially localized near CD8⁺ T cells together with IFN‐responsive microglial populations expressing Stat1, Ifit3, and Usp1 (Kaya et al. 2022). Importantly, Rag1‐deficient mice lacking functional lymphocytes exhibited marked reductions in IFN‐responsive OL states, activated microglia, and OL loss, suggesting that adaptive immune cells actively contribute to pathological OLC remodeling within chronic inflammatory white matter environments (Kaya et al. 2022). This finding provides important mechanistic evidence that CD8⁺ T cell‐driven IFN signaling is a conserved driver of pathological OLC state transitions across neuroinflammatory contexts. Whether this mechanism operates equivalently in human MS—particularly in chronic active versus inactive lesion subtypes—remains an important open question.

7. B Cells and OLCs in MS

B cells, key antigen‐presenting cells (APCs), efficiently recognize antigens via B cell receptors (BCRs) and constitutively express MHC class II together with co‐stimulatory molecules such as CD40, CD80, and CD86 (Zamvil and Hauser 2021; Koike et al. 2019; Zuccarino‐Catania et al. 2014; Lim et al. 2012). Optimal APC function occurs when BCR specificity aligns with T cell reactivity (Häusser‐Kinzel and Weber 2019). Antigen presentation activates T cells, driving B cell proliferation, differentiation into plasma cells, and antibody production. Persistent oligoclonal immunoglobulins in MS CSF underscore B cell pathological relevance (Häusser‐Kinzel and Weber 2019; Link and Huang 2006).

Meningeal B cells follicle aggregation correlates with cortical pathology (Magliozzi et al. 2007). Additionally, B cells promote MS through pro‐inflammatory cytokine (IL‐6, IL‐15, TNF, GM‐CSF) (Li, Patterson, and Bar‐Or 2018). B cell‐derived IL‐15 enhances CD8+ T cell cytotoxicity, contributing to OL and neuronal death (Schneider et al. 2011). In EAE, GM‐CSF drives chronic inflammation and demyelination (McQualter et al. 2001). In the culture system, under demyelinating conditions, Ig treatment augmented remyelination and differentiation of cultured OPCs; however, genetic deletion of B cells aggravated demyelination of OPCs in the CPZ‐induced demyelination model (Li et al. 2023). Similarly, exosome‐enriched fractions obtained from blood B cells derived from patients with MS triggered OL death (Benjamins et al. 2019). Moreover, in cultured B cells from patients with RRMS, B cell conditioned media induced OL death (Lisak et al. 2012). Based on these results, released factors from B cells have cytotoxic properties toward OLs; consequently, they participate in OL death (Touil et al. 2023). To date, most studies on B cells and OLCs have focused on how B cell‐derived factors influence OLC survival and differentiation. However, emerging evidence suggests that OLCs themselves can modulate multiple immune cell subsets, including B cells, through antigen presentation and cytokine release. Therapeutic regimens that selectively modulate B cell‐OLC interactions, rather than globally depleting B cells, may therefore provide more precise strategies tailored to MS subtype and disease stage.

8. Monocytes/Monocyte‐Derived Macrophages and OLCs in MS

It has become clear that, in addition to T and B cells, monocytes also play a major role in severe MS by directly stripping away the myelin sheath. T cells stimulate a specific type of monocyte to initiate an attack on myelin, including CXCL10⁺ monocytic cells. CXCL10⁺ monocytic cells produce plenty of IL‐1β that causes BBB dysfunction, allowing the penetration of immune cells from the bloodstream into the CNS, resulting in exacerbation of MS symptoms (Giladi et al. 2020). In EAE, infiltrating monocytes differentiate into macrophages, leading to the accumulation of monocyte‐derived macrophages (MoDMs) at the onset of the disease. Notably, these MDMs were found exclusively in contact with demyelinated axonal units, particularly at the nodes of Ranvier. In contrast, microglia‐derived macrophages (MiDMs) primarily focused on clearing debris. This distinction suggests that MoDMs are primarily responsible for initiating demyelination and possess unique characteristics that set them apart from MiDMs (Yamasaki et al. 2014). Additionally, compromised phagocytosis of myelin debris was found in MDMs derived from patients with MS (Healy et al. 2017). In addition, it is reported that there is a strong correlation between the infiltration of blood‐derived monocytes into the CNS and the progression to the paralytic stage of EAE (Ajami et al. 2011). This study demonstrated that blocking the recruitment of monocytes to the CNS through chemokine receptor inhibition effectively halted EAE progression, underscoring the essential role of these infiltrating cells in driving the disease. Altogether, these findings suggest that therapeutic approaches targeting the specific inhibition of monocyte infiltration into the CNS could be effective in protecting OLCs and controlling disease progression in MS.

In addition, monocytes from MS patients produced higher levels of pro‐inflammatory cytokines including TNF‐α and IL‐1β, compared to healthy controls, and that this increased cytokine secretion correlated with disease activity. These findings highlight that monocytes play a pivotal role in the inflammatory process underlying MS (Rudick and Ransohoff 1992). Also, monocyte‐derived IL‐6 and IL‐12 are involved in inflammatory responses in MS (Filion et al. 2003). Although research regarding the interaction between monocytes and OLCs is limited, it is worthwhile that future studies focusing on modulation of this interaction might solve the problems observed in MS pathology.

9. Current Therapeutics in MS, Limitations, and Future Directions

Importantly, most currently approved MS therapies primarily function by suppressing immune‐mediated inflammatory damage, thereby preserving OLs and axons from further degeneration (Ridley et al. 2024; Dang et al. 2025). However, despite their efficacy in reducing relapse frequency and inflammatory activity, none of the currently approved therapies directly promote OL differentiation, remyelination, or regeneration of damaged myelin sheaths. This therapeutic gap may contribute to the persistent neurological disability and incomplete functional recovery observed in many patients, particularly in progressive stages of MS where neurodegeneration and remyelination failure become dominant pathological features. Preclinical research using various EAE models with different strains and immunization protocols has elucidated key mechanisms underlying MS pathogenesis and identified several molecular targets (Komiyama et al. 2006; Kuerten et al. 2007; Fillatreau et al. 2002; Yoshizaki et al. 2012; Bebo Jr. et al. 1996; Ignatius Arokia Doss et al. 2015; Dang et al. 2015; Krishnamoorthy et al. 2009; Haak et al. 2009). These experimental insights have, in turn, facilitated the development of disease‐modifying therapies that have been translated into clinical practice.

Through animal studies, research on MS has achieved substantial advancements leading to the approval of several drugs for clinical use (Zamvil and Hauser 2021; Schulze‐Topphoff et al. 2016; Turner et al. 2015; Merrill et al. 2009; Teitelbaum et al. 1996). However, despite these achievements, there have been critical limitations where translation has not yielded positive results. One of the remarkable instances is TNF‐α signaling, which has been implicated in both EAE and MS. As mentioned above, TNF‐α expression correlates with disease severity in MS, and inhibition of TNF‐α ameliorated disease progression in rat EAE models (Chu et al. 2021; Martino et al. 1997; Klinkert et al. 1997; Valentin‐Torres et al. 2016). However, it is noteworthy that clinical trials involving the TNF‐α blocker infliximab have been associated with a worsening of symptoms in MS patients. Similarly, laquinimod, that suppresses the pro‐inflammatory properties of Th17 cells and VLA‐4‐mediated leukocyte adhesion, showed promising outcomes in EAE but was associated with adverse effects including abnormal liver function, headache, myocardial infarction, and pericarditis (Haggiag et al. 2013). Additionally, teriflunomide, which inhibits mitochondrial dihydro‐orotate dehydrogenase, has also been associated with adverse effects, such as increased levels of alanine aminotransferase, headache, and gastrointestinal symptoms (Bar‐Or et al. 2014).

To date, several drugs for MS have been developed and approved by FDA or clinical phase trials, which target different mechanism pathways (Table 4). Nevertheless, substantial limitations remain. FDA‐approved therapies neither reverse established neurodegeneration nor completely halt disease progression, but rather slow disease progression and mitigate clinical symptoms (Hauser and Cree 2020). Importantly, most currently available agents primarily modulate peripheral immune cell trafficking or effector functions, while exerting only indirect or poorly defined effects on OLC biology and the regenerative capacity of demyelinated lesions. Bridging this gap will likely require therapies that directly promote OPC proliferation and differentiation or reshape inflammatory environments to restore pro‐remyelinating and OLC‐supportive niches. Notably, several recent therapeutic approaches have attempted to directly enhance remyelination rather than solely suppressing inflammation. For example, opicinumab, an anti‐LINGO‐1 monoclonal antibody designed to promote OPC differentiation and remyelination, demonstrated limited clinical efficacy in Phase II trials despite promising preclinical findings (Cadavid et al. 2019). These outcomes further highlight the translational challenges associated with promoting effective remyelination in MS patients.

TABLE 4.

Current MS therapeutics and development.

Type	Mechanism of action	Possible implication on OLCs	Approval by FDA	References
Interferon Beta‐1a (Avonex, Rebif)	Modulates immune response by reducing inflammation, regulating the BBB's permeability, and inhibiting T‐cell activation.	Indirectly protects OLs by reducing inflammatory cytokines and immune‐mediated injury; no clear evidence for direct OPC differentiation or remyelination	Yes	(Kleinschnitz et al. 2015; Dhib‐Jalbut and Marks 2010; Marziniak and Meuth 2014)
Interferon beta‐1b (Betaseron, Extavia)	Similar to interferon Beta‐1a, it modulates immune response to reduce inflammation and T‐cell activation.		Yes	(Dhib‐Jalbut and Marks 2010; Marziniak and Meuth 2014; IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group 1995)
Glatiramer acetate (Copaxone)	Mimics MBP, diverting immune response away from myelin and promoting regulatory T‐cell production.	May promote neuroprotective immune environments supportive of OL survival; limited direct evidence for remyelination	Yes	(Johnson et al. 1998; Farina et al. 2005; Schrempf and Ziemssen 2007)
Natalizumab (Tysabri)	Monoclonal antibody that inhibits α4‐integrin, preventing immune cells from crossing the BBB.	Reduces leukocyte infiltration and secondary inflammatory OL injury; no established direct remyelinating effect	Yes	(Wiendl et al. 2024; Goodin et al. 2008; Buron et al. 2023)
Fingolimod (Gilenya)	Sphingosine‐1‐phosphate receptor modulator that sequesters lymphocytes in lymph nodes, reducing their migration to the CNS.	May enhance OL survival and process extension through S1P signaling; limited evidence for robust remyelination	Yes	(Menendez et al. 2023; Meca‐Lallana et al. 2021; Mehling et al. 2011)
Teriflunomide (Aubagio)	Inhibits dihydroorotate dehydrogenase, reducing pyrimidine synthesis and limiting rapidly dividing T and B cells.	Reduces inflammatory stress on OLCs; no direct evidence for OPC differentiation	Yes	(Bar‐Or et al. 2014; Chitnis et al. 2024)
Dimethyl Fumarate (Tecfidera)	Activates the Nrf2 pathway, providing anti‐inflammatory and neuroprotective effects.	Reduces oxidative stress and protects OLs vis Nrf2 activation; no established direct remyelination effect	Yes	(Schulze‐Topphoff et al. 2016; Okuda et al. 2023; Huang et al. 2015)
Alemtuzumab	Monoclonal antibody targeting CD52 on lymphocytes, leading to their depletion and subsequent repopulation.	In directly preserves myelin and axons through immune cell depletion; direct effects on OLC biology remain unclear	Yes	(Roos et al. 2024; Chitnis et al. 2025; Rolla et al. 2020; Li, Richards, et al. 2018)
Ocrelizumab (Ocrevus)	Monoclonal antibody targeting CD20 on B cells, leading to their depletion.	Reduces inflammatory response; no direct evidence for OLCs	Yes	(Kolind et al. 2023; Abbadessa et al. 2023)
Siponimod (Mayzent)	Selective sphingosine‐1‐phosphate receptor modulator, similar to fingolimod but with selectivity for S1P1 and S1P5 receptors.	May support remyelination and OL survival through S1P5 receptor signaling in oligodendrocytes; evidence for direct protective effects on OLs	Yes	(Stavrogianni et al. 2024; Hendek et al. 2024; Behrangi et al. 2022; Chaudhry et al. 2017)
Cladribine (Mavenclad)	Purine nucleoside analog that selectively targets and depletes lymphocytes.	Primarily acts through immune reconstitution and reduction of inflammatory injury; direct effects on OLCs are unclear	Yes	(Brochet et al. 2024; Arena et al. 2024)
Ozanimod (Zeposia)	Sphingosine‐1‐phosphate receptor modulator that reduces lymphocyte migration into the CNS.	May indirectly preserve OL integrity through reduction of CNS inflammatory infiltration; direct remyelinating effects remain unclear	Yes	(Paul et al. 2024; Nie and Syed 2024; Naismith et al. 2024)
Ofatumumab (Kesimpta)	Monoclonal antibody targeting CD20 on B cells, leading to their depletion.	Indirectly preserves myelin integrity through CD20+ B cell depletion; no established direct effects on OPC differentiation	Yes	(Mimori et al. 2025; Ciccarese et al. 2025; Hauser et al. 2026)
Ponesimod (Ponvory)	Selective sphingosine‐1‐phosphate receptor 1 (S1P1) modulator, reducing lymphocyte egress from lymph nodes.	May indirectly reduce inflammatory‐mediated OL injury via modulation of lymphocyte trafficking; direct regenerative effects remain undefined	Yes	(Kruger et al. 2023; Freedman et al. 2022)
Ublituximab (Briumvi)	Glycoengineered chimeric monoclonal antibody targeting CD20 on B cells, leading to their depletion.	Indirectly limits inflammatory demyelination through B cell depletion; direct effects on OLC biology remain unknown	Y	(Moloney et al. 2024; Oh and Bar‐Or 2022; Fox et al. 2021)
Tolebrutinib	Bruton's tyrosine kinase (BTK) inhibitor; modulates B‐cell and microglia activity to reduce neuroinflammation. Irreversible covalent BTKi, hepatotoxicity concerns emerged during clinical development.	May modulate microglial inflammatory states and create a permissive remyelinating environment	No	(Turner et al. 2024; Zurmati and Khan 2023; Reich et al. 2021)
			Phase III trial
Fenebrutinib	Bruton's tyrosine kinase (BTK) inhibitor; modulates B‐cell and myeloid cells to reduce neuroinflammation. Reversible covalent BTKi.	Potential indirect support for remyelination through modulation of B cells and myeloid cells	No	(Bar‐Or et al. 2025)
			Phase III trial
Frexalimab	Anti‐CD40 ligand monoclonal antibody; modulates immune response by inhibiting the CD40‐CD40L interaction.	May indirectly reduce inflammatory damage to OLCs through modulation of CD40‐CD40L signaling; remyelinating effects remain unknown	No	(Vermersch et al. 2024; Carvalho 2023)
			Phase II trial
IMU‐838	Dihydroorotate dehydrogenase (DHODH) inhibitor; selectively modulates activated T and B cells to reduce neuroinflammation.	May indirectly preserve OLs through selective suppression of activated immune responses; direct remyelinating effects remain unknown	No	(Sharma et al. 2022; Muehler et al. 2020; Hahn et al. 2020)
			Phase III trial
Masitinib	Tyrosine kinase inhibitor; targets mast cells and microglia to modulate the innate immune system, potentially reducing neuroinflammation.	May modulate innate immune activation, including mast cells and microglia, thereby potentially reducing inflammatory OL injury	No	(Vermersch et al. 2022, 2012; Arsenault et al. 2022)
			Phase III trial
Simvastatin	Statin; exhibits potential neuroprotective and anti‐inflammatory effects, possibly reducing brain atrophy in MS patients.	May exert neuroprotective and anti‐oxidative effects on OLs; remyelination efficacy remains uncertain	No	(Filippi and Rocca 2017; Chan et al. 2017; Sorensen et al. 2011; Vollmer et al. 2004)
			Phase III trial

Beyond agents that directly target OPC differentiation, converging evidence from recent single‐cell and spatial transcriptomic studies has revealed several mechanistically distinct and therapeutically actionable pathways operating within CALs that merit consideration in next‐generation MS therapy design. First, the identification of a pathogenic inflammatory niche at the CAL rim—defined by CD8⁺ T cell co‐localization with MIMS exhibiting impaired ABCA1/G1‐mediated cholesterol efflux and foam cell formation—positions the microglial sterol metabolism pathway as a novel pharmacological target (Feng et al. 2025). Notably, pharmacological targeting of sterol metabolism in EAE reduced foam cell burden and attenuated inflammatory demyelination, providing preclinical proof‐of‐concept for this approach (Feng et al. 2025). Second, the discovery that senescent microglia accumulate in demyelinated lesions and suppress OLC remyelination through SASP‐mediated CCL11 secretion and cholesterol crystal accumulation suggests that senolytic strategies—or selective blockade of SASP effectors such as CCL11—could restore remyelination capacity, particularly in aging patients with progressive MS (Gross et al. 2025). Third, spatial transcriptomic analysis of post‐mortem MS brain tissue and patient‐derived hiPSC neural organoids demonstrated that inflammation‐induced microglial senescence can be partially reversed by CNS‐penetrant anti‐inflammatory treatment (Fagiani et al. 2025). Finally, the demonstration that age‐associated impairment of remyelination reflects a dysregulation of sequential microglial state transitions—including delayed appearance of a pro‐remyelinating, myelin transcript‐enriched resolved microglial state—suggests that therapeutically orchestrating timely microglial state transitions may be particularly relevant in elderly MS patients and in progressive disease stages where endogenous repair is most severely compromised (Zia et al. 2025). Collectively, these findings argue that future therapeutic strategies should move beyond broad immunosuppression and instead target the specific microglial metabolic, senescent, and state‐transitional dysfunctions that directly obstruct OLC‐mediated remyelination within chronic demyelinating lesions.

Another major limitation is the lack of specificity in targeting the immune response. Many therapies broadly suppress the immune system, increasing susceptibility to infections and secondary autoimmune complications (Fugger et al. 2020). For instance, while B‐cell depletion therapies such as ocrelizumab effectively reduce disease activity, they can also increase the risk of latent infection reactivation and reduce vaccine efficacy (Flynn and Gerriets 2025). This broad immunosuppression is particularly concerning for patients requiring long‐term treatment. Furthermore, current therapies demonstrate limited efficacy in progressive forms of MS, such as primary progressive MS (PPMS) and secondary progressive MS (SPMS) (Watson et al. 2023). In these disease stages, the inflammatory activity becomes less prominent, while neurodegeneration, chronic demyelination, axonal loss, and remyelination failure become increasingly prominent (Gajofatto and Benedetti 2015). However, most current therapies remain focused on immune modulation rather than actively restoring damaged myelin or enhancing the regenerative repair process (Alizadeh et al. 2015). Consequently, many therapies effective in relapsing–remitting MS (RRMS) fail to demonstrate substantial benefits in progressive cases (Dutta and Trapp 2014).

In addition, the high cost of disease‐modifying therapies limits accessibility for many patients (Hartung et al. 2015), and current therapies are also associated with severe adverse effects, including flu‐like symptoms, liver dysfunction, and severe adverse events such as progressive multifocal leukoencephalopathy (PML) (Rafiee Zadeh, Ghadimi, et al. 2019; Rafiee Zadeh, Askari, et al. 2019). Collectively, these limitations underscore the urgent need for therapeutic strategies that not only suppress inflammation but also directly promote remyelination, OL regeneration, and long‐term neuroprotection.

This review highlights the complex interplay between OLCs and surrounding CNS‐resident and infiltrating immune cells, emphasizing how these interactions critically shape demyelination, remyelination, and disease progression in MS (Figure 5). Therefore, future therapeutic strategies should prioritize precise immunomodulation while simultaneously targeting regenerative pathways that enhance OLC survival, OPC differentiation, remyelination, and axonal protection within chronic demyelinating lesions.

FIGURE 5.

Perspectives on future treatments for MS. Conventional therapies for MS have focused on a single factor or suppressing immune response without considering neuronal microenvironment. Therefore, these limitations lead to undesirable outcomes. To overcome these issues, it is necessary to understand OLCs' biology and their connection between CNS cells or infiltrating peripheral immune cells. OLCs interact with different types of cells across its stages, including OPC proliferation (1), migration to the demyelinating site (2), OPC differentiation (3), and eventually remyelination (4). Future research that comprehends these interactions could offer a promising strategy for treating MS.

10. Conclusion

MS remains a formidable neurodegenerative and autoimmune disease, characterized by widespread demyelination, chronic neuroinflammation, and progressive axonal loss. Despite substantial advances in disease‐modifying therapies, current treatments primarily target peripheral and CNS immune responses, effectively reducing relapse rates and new lesion formation; yet they only partially prevent long‐term disability and lack the capacity to promote remyelination or repair established damage.

This review reframes OLCs not as passive victims of inflammation but as active participants in shaping the lesion microenvironment. OLCs engage in bidirectional crosstalk with neurons, astrocytes, microglia, and infiltrating immune cells across all stages of the disease. Pathological conditions reprogram OLCs into stress‐ and immune‐responsive states that suppress OPC proliferation, migration, and differentiation, while OLCs in turn modulate microglial activation, antigen presentation to T cells, and BBB integrity—interactions that collectively perpetuate demyelination and constrain endogenous repair.

Recent single‐cell and spatial transcriptomic studies have identified specific and therapeutically actionable mechanisms operating within chronic active lesions, including microglial lipid metabolic dysfunction driven by impaired ABCA1/G1‐mediated cholesterol efflux, senescence‐associated suppression of OLC remyelination through SASP‐mediated CCL11 secretion, and age‐dependent dysregulation of sequential microglial state transitions. These findings underscore that restoring OLC repair capacity will require targeting the lesion microenvironment directly, rather than relying solely on peripheral immune suppression.

Future therapeutic strategies should therefore combine selective modulation of pathogenic immune cell subsets with approaches that directly restore OLC function, promote OPC differentiation, and support myelin regeneration. Defining the molecular logic of OLC‐centered communication networks and translating this knowledge into mechanism‐anchored interventions may ultimately offer the best opportunity for achieving durable remission and improved functional recovery in MS patients.

Author Contributions

Design, conceptualization: J.P. and F.G. Funding acquisition and supervision: J.P. and F.G. Writing – original draft: J.P. Writing – review and editing: J.P. S.Y.C. and F.G. Figures and tables: J.P. and S.Y.C. Manuscript finalization: F.G. All authors read and approved the final manuscript. J.P. and S.Y.C. contributed equally to this work as first authors.

Funding

This work was supported by the National Institute of Neurological Disorder and Stroke (NINDS) (R01NS123080, R01NS123165, R01NS134887); Shriners Hospital for Children (84311‐NCA‐24); and this paper was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIT) (No. 2020R1C1C1010613).

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.