Metabolic reprogramming of oligodendrocyte lineage cells in ischemic stroke: Insights from literature review and a single-cell transcriptomic re-analysis

Abstract

Ischemic stroke (IS) causes white matter (WM) injury and disrupts myelin integrity, contributing to long-term cognitive dysfunction. Oligodendrocyte lineage cells, particularly oligodendrocyte precursor cells (OPCs), are essential for post-stroke remyelination, yet their survival, differentiation, and myelin-forming capacity are highly dependent on metabolic state. However, a systematic overview of these metabolic changes post-stroke is still lacking. Here, we review current knowledge on the crosstalk between classical pathways and oligodendrocyte lineage metabolism in IS, integrating evidence from recent studies and complementing them with a re-analysis of three independent single-cell RNA sequencing (scRNA-seq) datasets from mouse stroke models covering hyperacute, acute, and chronic recovery phases. This re-analysis highlighted stage-specific alterations in oxidative phosphorylation, inositol phosphate metabolism, and sphingolipid metabolism within OPCs, alongside activation of cholesterol biosynthesis in mature oligodendrocytes (OLs). These findings are consistent with evidence linking these pathways to oligodendrocyte lineage progression and WM repair. Together, the literature and re-analysis support the notion that oligodendrocyte lineage metabolism is an important regulator of post-stroke remyelination and may provide potential therapeutic targets for promoting cognitive function.

Keywords

Ischemic stroke metabolic pathways oligodendrocyte precursor cells oligodendrocytes single-cell transcriptomics

Introduction

Ischemic stroke (IS), the second leading cause of long-term disability and mortality worldwide, is caused by a sudden and critical reduction in cerebral blood flow, typically due to arterial occlusion.¹ Beyond acute neuronal injury, IS also triggers long-term cognitive dysfunction. Clinically, the severity of post-stroke cognitive impairment (PSCI) is often underestimated. PSCI affects up to 60% of stroke survivors within the first year, with approximately one-third eventually progressing to dementia.^2,3 Effective prevention of PSCI remains a major therapeutic gap in stroke treatment.⁴ There is a strong association between white matter (WM) injury and PSCI which is linked to poor outcomes in IS patients.^5–8 Brain scans also reveal that WM injury can continue for weeks or months after the stroke.⁹ Therefore, new treatments should focus on protecting WM to help patients improve functional recovery.

Within the WM, oligodendrocyte lineage cells including oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs) are key components, serving the essential functions of myelin production, maintenance, and regeneration.¹⁰ Mature OLs are the primary myelinating cells in the central nervous system (CNS), responsible for maintaining myelin sheath integrity and providing axonal support.¹¹ OPCs constitute ~5%–8% of glial cells in the adult CNS,¹² and retain the capacity for self-renewal and differentiation into OLs, thereby contributing to myelinogenesis during development and remyelination following injury.^13,14 Under certain conditions, OPCs can also differentiate into astrocytes and Schwann-like cells.^15–17 Together, oligodendrocyte lineage cells form a dynamic cellular system that supports WM maintenance and repair after IS.

The high energy demands required to sustain their functions render oligodendrocyte lineage cells highly vulnerable to energy deprivation, leading to severe cellular damage following IS.^18,19 Disruption of metabolic state can impair OPCs survival, proliferation, and differentiation, while also compromising OL-mediated myelin maintenance and axonal support.²⁰ However, due to their relatively low abundance and the technical challenges associated with isolating OPCs and OLs from brain tissue, in vivo investigations of their metabolic changes after IS remain limited. Thus, in addition to summarizing the existing literature, we also re-analyzed three scRNA-seq datasets from mouse models of IS, covering multiple time points from hyperacute, acute, and chronic post-stroke stages. We harmonized transcriptomic profiles across datasets to systematically examine metabolic changes in OLs and OPCs. This integrated transcriptional landscape provides insights for understanding how metabolic reprogramming of oligodendrocyte lineage cells may influence WM injury and repair after IS. In this review, we summarize the current knowledge on the roles of the oligodendrocyte lineage cells in IS, integrate our scRNA-seq re-analysis with a specific focus on their unique metabolic adaptations and their translational potential for targeted therapeutic interventions.

Signaling and metabolic regulation of oligodendrocyte lineage cells following IS

Based on the studies summarized in Table 1, a range of preclinical IS models—including transient and permanent middle cerebral artery occlusion (MCAO) as well as photothrombosis (PT) stroke in mice and rats—have revealed signaling and metabolic pathways that shape the fate of oligodendrocyte lineage cells. Key pathways including LINGO-1, Shh–Gli1, LRP1–PPARγ, Nrf2, Notch signaling pathway, and more, each of which have been associated with oligodendrocyte lineage cells proliferation, migration, differentiation, or remyelination. Injury-related modulators such as BNIP3, Nec-1, CB1, TGF-α, and miR-23a-5p have been implicated in modulating OPCs survival after IS. These IS studies highlight diverse signaling mechanisms that shape OPCs and OLs behavior.

Table 1.

Overview of pathways regulating oligodendrocyte lineage cells following stroke.

Author (year)	Model	Species	Mechanisms	Functional outcome
Wang (2025)⁷¹	tMCAO (90)	Mouse	β-Catenin↑	Inflammation↓
Liu (2019)⁷²	tMCAO (60)	Mouse	CD147↓	Oligodendrogenesis↑
Cheng (2024)²⁷	tMCAO (30)	Mouse	M1R cko/Olig2 cko	Remyelination↑/↓
Strecker (2024)⁷³	PT stroke	Mouse	LINGO-1↓	Remyelination↑, axonal growth↑, OPCs proliferation↑
Owino (2021)⁷⁴	Sensorimotor cortex IS	Mouse	GPR37^-/-	Reactivity of OPCs↓
Dai (2020)⁷⁵	tMCAO (60)	Mouse	TGFα↑	Protect OPCs and oligodendrocytes from death
Shibahara (2023)⁷⁶	pMCAO	Mouse	Laminin a2↑	OPCs differentiation↑
Guan (2022)⁷⁷	tMCAO (60)	Mouse	BNIP3↓	OPCs loss↓
Li (2022)⁷⁸	tMCAO (12)	Mouse	Nrf2↑	OPCs migration↑, differentiation↑
Wang (2024)⁷⁹	tMCAO (60)	Mouse	LRP1↑, PPARγ↑	OPCs differentiation↑, remyelination↑
Raffaele (2021)⁸⁰	pMCAO	Mouse	tmTNF in EVs from microglia	GPR17⁺ OPCs maturation
Liu (2022)⁸¹	tMCAO (60)	Mouse	EphA4/Ephexin-1/RhoA/ROCK pathway	Proliferation↑, differentiation↓, remyelination↓
Zhao (2022)⁸²	tMCAO (120)	Rat	Shh–Gli1↓	Myelin repair↓, Olig1 expression↓
Yu (2021)⁸³	tMCAO (60)	Rat	Shh–Gli1↑	OPCs proliferation↑, differentiation↑, migration↑
Choi (2023)⁸⁴	Focal WMS	Mouse	HMGB1/TLR2–ERK1/2–FAK pathway↑	OPCs migration↑
Li (2021)⁸⁵	tMCAO (60)	Mouse	CXCL12↑, Netrin-1/DCC axis	Oligodendrogenesis↑, neurite growth↑, synaptogenesis↑
Ye (2024)⁸⁶	ICH	Rat	Ribosomal signaling↑	OPCs proliferation↑
Wang (2020)⁸⁷	tMCAO (90)	Mouse	OPCs transplantation	Wnt/β-catenin pathway↑, blood–brain barrier leakage↓
Zhuang (2025)⁸⁸	pMCAO	Rat	Notch signaling pathway↓	Oligodendrogenesis↑, remyelination↑
Chen (2018)⁸⁹	tMCAO (60)	Mouse	Nec-1 inhibiting RIPK1, RIPK3, MLKL, and P-MLKL	OPCs survival↑
Sun (2013)⁹⁰	pMCAO	Rat	WIN55,212-2 activates CB1	OPCs survival and proliferation↑
Sun (2012)⁹¹	tMCAO (120)	Rat	WIN55,212-2 activates CB1R and regulating p-ERK1/2	OPCs differentiation and remyelination↑
Li (2022)⁹²	tMCAO (90)	Mouse	miR-23a-5p from M2-EVs	OPCs proliferation, survival, and maturation↑
Xu (2023)⁹³	tMCAO (60)	Rat	Physical exercise/TREM2↑	Remyelination↑, OPCs differentiation↑
Zhang (2023)⁹⁴	pMCAO	Mouse, 20 months	Transplanted human MSCs	Oligodendrogenesis↑
Zarriello (2019)⁹⁵	OGD/R	/	T_regs	OPCs differentiation↑
Shen (2007)⁹⁶	tMCAO (120)	Rat	BMSCs	The number of OPCs↑
Zhou (2018)³²	tMCAO (60)	Mouse	MCT1↑	Redistribution of energy substrates
Miyamoto (2013)⁶⁵	Cerebral chronic hypoperfusion model	Mouse	pCREB↓	Oligodendrocyte regeneration↓
Zhang (2016)⁹⁷	tMCAO (60)	Mouse	n-3 PUFAs	Oligodendrogenesis↑

tMCAO: transient middle cerebral artery occlusion; PT: photothrombotic; IS: ischemic stroke; pMCAO: permanent middle cerebral artery occlusion; WMS: white matter stroke; ICH: intracerebral hemorrhage; OGD/R: oxygen–glucose deprivation/reoxygenation; BMSCs: bone marrow mesenchymal stem cells; EVs: extracellular vesicles; PUFAs: polyunsaturated fatty acids.

Accumulating evidence from other neurological diseases suggests that many of these pathways are closely associated with metabolic processes, which are essential for maintaining oligodendrocyte lineage cells function. For instance, Nrf2 is widely recognized for its role in regulating cellular redox homeostasis and mitochondrial function, thereby influencing oxidative metabolism under stress conditions.²¹ Similarly, LRP1–PPARγ signaling has been linked to lipid metabolism and fatty acid oxidation, processes that are essential for myelin synthesis.^22,23 Notch signaling, beyond its typical role in cell fate determination, has also been implicated in the regulation of glycolysis and mitochondrial activity.²⁴ In addition, Wnt/β-catenin signaling has been shown to coordinate glucose metabolism and anabolic pathways, thereby supporting biosynthetic demands during differentiation.²⁵ Collectively, although these pathways are described as regulators of oligodendrocyte lineage cells function after IS, evidence from other diseases indicates that they are frequently coupled to metabolic processes, raising the possibility that metabolic regulation represents a shared downstream mechanism underlying their effects.

To understand how this potential signaling-metabolism crosstalk translates into functional neuroprotection, it is essential to examine the fundamental metabolic demands of WM repair. This repair process can be modulated by the availability of myelin substrates and energy supply.^26–28 Therefore, metabolic reprogramming is significant to promote WM recovery after IS.^29,30 Due to the high ATP requirements of myelination, oligodendrocyte lineage cells exhibit a specific preference for energy substrates, utilizing lactate for lipid synthesis at a significantly higher rate than neurons and astrocytes.³¹ OPCs rely on monocarboxylate transporter 1 (MCT1) for lactate uptake, which is upregulated following stroke, whereas its expression in mature OLs remains unchanged.³² The distinct MCT1 expression profiles between OPCs and mature OLs dictate their differential vulnerabilities to energy deprivation, indicating that energy substrate redistribution is a key determinant of WM damage.

The metabolic response of OPCs to ischemia also involves active regulatory mechanisms. To adapt to low-glucose environments, OPCs utilize a specific intrinsic metabolic checkpoint. ALDOC, their predominant intracellular aldolase isozyme, undergoes physiological acetylation at the K14 residue, which prevents the activation of the downstream AMPK pathway by low-glucose signals.³³ By bypassing AMPK-mediated energetic dormancy, OPCs maintain the proliferation and differentiation capacities required for initiating repair within the ischemic penumbra. Therefore, metabolic shifts serve as regulatory mechanisms that drive WM recovery after IS.

Nevertheless, a comprehensive and systematic evaluation of global metabolic reprogramming in oligodendrocyte lineage cells following IS is still lacking. To bridge this gap, evidence from other neurological diseases provides important complementary insights into the metabolic regulation of OPCs and OLs. Lipid homeostasis, for example, is essential for oligodendrocyte lineage cells differentiation and myelination.³⁴ A recent study using a seipin-deficient mouse model, which mimics features of metabolic neurological disorders, demonstrated that seipin loss disrupts lipid homeostasis, leading to abnormal lipid droplet morphology, impaired OPCs differentiation, defective myelination, and subsequent cognitive and motor impairments.³⁴ In the context of demyelinating diseases such as multiple sclerosis (MS), a metabolomic study revealed that taurine markedly promotes OPCs differentiation by supporting intracellular serine pools required for glycosphingolipid synthesis and myelin formation.³⁵ Furthermore, a recent review focusing on neurodegenerative diseases including MS, Alzheimer’s disease, and Parkinson’s disease proposed that oxidative and carbonyl stress interfere with mitochondrial function and lipid biosynthesis, thereby impeding the transcriptional and metabolic programs essential for OPCs maturation.²⁹ Together, findings from related neurological disorders emphasize the critical role of lipid metabolic networks in the oligodendrocyte lineage cells, suggesting that targeting lipid homeostasis may similarly drive WM recovery following IS.

In summary, current literature indicates that various signaling pathways can regulate the survival and function of oligodendrocyte lineage cells after IS. Notably, several of these pathways also exert metabolic regulatory effects. Furthermore, evidence from IS and other CNS disorders suggests that lactate metabolism and lipid homeostasis are critical determinants of oligodendrocyte lineage cells-mediated WM repair. However, direct mechanistic studies investigating the metabolic reprogramming of the oligodendrocyte lineage cells following IS remain unexplored. Therefore, using public scRNA-seq datasets, we systematically analyzed the metabolic reprogramming of the oligodendrocyte lineage cells following IS.

Re-analysis of public scRNA-seq datasets

We examined scRNA-seq datasets from mouse models of IS that were available by March 2025. In total, three datasets comprising 10 samples and ~96,000 cells across several post-stroke time points and two stroke models were included. The characteristics of these three datasets are summarized in Table 2. To preserve biological heterogeneity across different stroke models, we analyzed the datasets independently rather than applying a global integration. While all control samples were batch-corrected and merged, the PT model and datasets from unmatched time points were processed as separate cohorts for dimensionality reduction, clustering, and differential expression. Integration was restricted strictly to the 3-day post-MCAO datasets. The quality control for the extracted data were shown in Figure 1(a). Using known cell markers, we identified 15 main cell populations from the clustering analysis (Figure 1(b) and (c)). The overall cellular composition for each condition is summarized in Figure 1(d). Subsequent analyses focused on OLs and OPCs, which showed distinct patterns of gene expression and metabolic pathway enrichment at different phases after IS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results of eight metabolic pathways for OLs and OPCs were shown in Figure 2.

Table 2.

The scRNA-seq studies included in this integrative analysis.

Study	Accession	Tissue	Technique	Intervention	Groups	Tissue section
Li et al.⁶⁸	PRJNA912889	Brain	10× Genomics	MCAO for 1 h	3, 12 h, and 3 days, sham	Isolated ipsilateral hemispheres from MCAO mice at 3, 12 h, and 3 days, sham mice (n = 4)
Zeng et al.⁷⁰	GSE227651	Brain	10× Genomics	MCAO for 1.5 h	1, 3, and 7 days, sham	Isolated ipsilateral hemispheres from MCAO mice at 1, 3, and 7 days, sham mice (n = 4)
Han et al.⁶⁹	CRA006645	Brain	10× Genomics	PT stroke	3 days, sham	Collected two separate sample pools from the peri-infarct areas of 10 PT mice and 10 sham mice, respectively (n = 2)

PT: photothrombotic; MCAO: middle cerebral artery occlusion.

Figure 1.

Quality control and cell annotation for the extracted data: (a) quality control after filtering, (b) the UMAP representation of the cells after correction and doublet removal, circularized, (c) a dot plot of the cell-type marker merge RNA data, and (d) cell component per cell type percent group by condition after annotation.

Figure 2.

KEGG enrichment results of eight metabolic pathways for OPCs and OLs. Red bubbles indicate upregulated or downregulated pathways, with dot size representing gene count and color intensity reflecting the adjusted p value: (a) downregulated pathways in different time-points within eight metabolic pathways for OPCs, (b) downregulated pathways in different time-points within eight metabolic pathways for OLs, (c) upregulated pathways in different time-points within eight metabolic pathways for OPCs, and (d) upregulated pathways in different time-points within eight metabolic pathways for OLs.

Hyperacute phase (3 and 12 h)

In the hyperacute phase (3 and 12 h), the OXPHOS pathway was strongly suppressed in OPCs (Figure 2(a)) and OLs (Figure 2(b)). Unlike mature OLs that rely on glycolysis, OPCs depend on OXPHOS to meet the high energy demands of proliferation and differentiation.^36,37 Therefore, suppression of OXPHOS may critically impair OPCs function. Our compound–reaction–enzyme–gene network analysis further confirmed that key mitochondrial enzymes, including Complex I, II, and V, were influenced in OPCs (Figure 3(a)). Although the glycolytic pathway appeared stable in OPCs, it may not be sufficient to support cell survival. This observation aligns with a previous finding that OPCs upregulate MCT1 expression following IS,³² suggesting that lactate may serve as a crucial alternative energy substrate for OPCs survival during the hyperacute phase.

Figure 3.

Compound-reaction-enzyme-gene networks for OPCs. The dark blue circle represents the key target genes, the orange hexagon represents the key metabolite, the green square represents the key enzymes, and the yellow square represents the reactions: (a) OXPHOS pathway at 3-h post-stroke, (b) inositol phosphate metabolism pathway at 3-h post-stroke, (c) sphingolipid metabolism pathway at 3-day post-stroke, and (d) sphingolipid metabolism pathway at 7-day post-stroke.

Furthermore, we observed that apart from OXPHOS, several lipid metabolic pathways, including sphingolipid metabolism, fatty acid elongation, and the biosynthesis of unsaturated fatty acids, were significantly downregulated in mature OLs in the hyperacute phase (Figure 2(b)). These findings suggest that, in response to IS induced energy depletion, mature OLs may undergo marked metabolic reprogramming by broadly suppressing energy-demanding lipid biosynthetic pathways.

In contrast, inositol phosphate metabolism was significantly activated in OPCs and OLs in the 3-h post stroke group (Supplement Figure 1). Key genes such as Plcb4, Itpkc, Pik3cb, and Pten were enriched in OPCs (Figure 3(b)). This pathway is critical for intracellular calcium homeostasis and signal transduction.^38–40 Although direct evidence is limited, the upregulation of these genes suggests a potential protective mechanism. For instance, Itpkc regulates IP3/IP4 levels, which may modulate calcium channels, thereby affecting cell migration.^41,42 Interestingly, we observed the simultaneous upregulation of Pten (which inhibits PI3K/Akt signaling) and Pik3cb (which activates it). This suggests a complex, dynamic regulation of the PI3K/Akt pathway, which plays a bidirectional role in IS.⁴³ Furthermore, since neuron-OPC synapses rely on Ca²⁺-dependent signaling,⁴⁴ the activation of inositol phosphate metabolism may enhance the ability of OPCs to receive neuronal inputs. This could be a crucial early step for activity-dependent remyelination.

Acute phase (1 and 3 days)

At 1-day post-stroke, we observed a significant upregulation of OXPHOS pathway both in OPCs (Figure 2(c)) and OLs (Figure 2(d)). This indicates that oligodendrocyte lineage cells might shift from an energy-deficient state to a recovery phase. This rapid restoration of mitochondrial function is likely essential for them to support WM repair.

At 1-day post-stroke, mature OLs responded to IS by rapidly activating cholesterol biosynthesis pathways which including terpenoid backbone and steroid biosynthesis (Supplement Figure 2). Given that cholesterol constitutes 25%–30% of myelin, this upregulation likely represents an endogenous repair mechanism to support remyelination and generate neuroprotective metabolites like coenzyme Q10.^45–47

By 1- and 3-day post-stroke, OPCs shifted toward metabolic recovery, marked by the activation of sphingolipid metabolism (Figure 2(c)). As a central intermediate of sphingolipid metabolism, physiological levels of ceramide are essential for myelination. Genes like Smpd2 and Sptlc1 were upregulated in the acute phase to generate ceramide (Figure 3(c)). Furthermore, its downstream metabolite, sphingosine-1-phosphate (S1P), actively promotes OPCs survival and differentiation.^48–50

Chronic phase (7 days)

Conversely, excessive ceramide accumulation, a pathological feature in IS patients, exerts potential neurotoxicity by triggering mitochondrial dysfunction and oxidative stress.^51–53 Given these adverse effects, the precise control of sphingolipid metabolism is vital. Interestingly, we observed a biphasic regulation of OPCs sphingolipid metabolism: an initial upregulation at 1- and 3-day post-stroke, followed by a significant downregulation at 7 days with genes like Smpd2 and Sptlc1 declined (Figure 3(d)). This late-stage downregulation indicates a protective negative feedback mechanism. This adaptation enables OPCs to avert ceramide-induced neurotoxicity during the chronic phase.

Conclusions

Specifically, our findings synthesize how stage-dependent metabolic shifts directly regulate distinct phases of oligodendrocyte lineage cells. In the early phase, the acute restoration of OXPHOS acts as an energetic checkpoint, providing the necessary ATP to overcome ischemia-induced cell-cycle arrest thereby enabling OPCs proliferation and supporting OLs recovery. Subsequently, the dynamic activation of inositol phosphate metabolism supports calcium-dependent signaling, which is essential for OPCs to sense neuronal signals and migrate toward demyelinated areas.⁵⁴ In the later recovery stages, the robust shift toward sphingolipid and cholesterol metabolism serves as a biosynthetic checkpoint. This late-stage reprogramming provides not only the massive structural lipids required for membrane wrapping⁵⁵ but also specific signaling molecules (such as S1P) that drive terminal differentiation and remyelination.⁵⁶

In summary, our analyses indicate that OPCs and mature OLs adopt distinct but coordinated metabolic programs during recovery from IS, reflecting their different functional roles in WM repair. Importantly, these findings suggest that metabolic reprogramming in OPCs is not merely a passive response to ischemic stress, but an active determinant of their functional state and fate.

Future directions

The oligodendrocyte lineage cells undergo distinct metabolic reprogramming following IS, suggesting that metabolic plasticity is a core driver of OPCs proliferation, migration, and remyelination. Regulators such as ATP synthase subunits, Itpkc, Pten, and S1P present viable intervention points to support cell survival and repair. Given that WM injury and failed remyelination largely contribute to long-term functional deficits, targeting these specific pathways may improve neurological recovery.

Translating these findings into clinical practice, however, poses significant challenges regarding cell-specific targeting and concentration control. While systemic AMPK activation offers acute neuroprotection,^57,58 it risks disrupting subsequent WM repair. Specifically, OPCs rely on ALDOC-mediated AMPK suppression to preserve their capacity for remyelination.³³ Metabolic substrates like palmitic acid and ceramides exhibit biphasic or toxic effects at high doses.^59,60 Therefore, localized delivery via CNS-targeted nanocarriers will be necessary to minimize off-target toxicity.⁶¹

Clinical heterogeneity further complicates metabolic interventions. OPCs regulatory networks and metabolic capacities decline with aging and exhibit sex-specific differences, which inevitably alter therapeutic response thresholds.^62–64 Spatial differences between the ischemic core and penumbra also dictate local metabolic demands. Future therapeutic designs will need to incorporate stratified models that account for age, sex, and specific stroke subtypes, such as isolated WM infarction.

Any metabolic therapy must also align with standard reperfusion timelines. While reperfusion restores oxygen and glucose, the concurrent surge in reactive oxygen species (ROS) damages OPCs mitochondria.^29,30 Early-stage interventions might therefore require mitochondrial protection via antioxidants or NRF2/PPAR-γ activation,^23,65 whereas later recovery phases would benefit from lipid metabolism modulation and substrate supplementation, such as taurine, to support remyelination.^35,66,67

Ultimately, generalized nutritional support or simple energy supplementation is insufficient to drive effective WM repair. Advancing these metabolic concepts into practical therapies will require integrating targeted delivery, patient stratification, and stage-specific timing. Future in vivo studies validating these dynamic shifts will be critical for developing targeted rehabilitation strategies.

Our study has several limitations. The included datasets varied in ischemia duration and had limited sample sizes, which may not capture the full spectrum of oligodendrocyte metabolic remodeling. Furthermore, scRNA-seq captures transcriptional activity, which does not always strictly correlate with direct metabolic flux. The lack of spatial transcriptomic data also restricts our ability to distinguish metabolic responses between the ischemic core, penumbra, and remote regions. Lastly, despite batch correction and baseline merging, cross-study technical variations remain a potential source of bias.

Supplemental Material

sj-docx-1-jcb-10.1177_0271678X261458133 – Supplemental material for Metabolic reprogramming of oligodendrocyte lineage cells in ischemic stroke: Insights from literature review and a single-cell transcriptomic re-analysis

Supplemental material, sj-docx-1-jcb-10.1177_0271678X261458133 for Metabolic reprogramming of oligodendrocyte lineage cells in ischemic stroke: Insights from literature review and a single-cell transcriptomic re-analysis by Huijia Zhuang, Xisha Tang, Yu Zhang, Yang Han, Zhiyu Huang, Juan Xin and Hai Yu in Journal of Cerebral Blood Flow & Metabolism

Footnotes

Acknowledgements

The authors acknowledge the use of publicly available scRNA-seq data from PRJNA912889, CRA006645, and GSE227651, originally published by Li et al.,⁶⁸ Han et al.,⁶⁹ and Zeng et al.⁷⁰

Author contributions

Hai Yu conceived and designed the study. Huijia Zhuang and Xisha Tang drafted the manuscript. Huijia Zhuang, Xisha Tang, and Yu Zhang performed the data analyze. Yang Han and Zhiyu Huang performed literature review and figure editing. Huijia Zhuang, Juan Xin, and Hai Yu revised and finalized the manuscript. All authors read and approved the final version of the paper.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Natural Science Foundation of China (82372208, 82072132, and 82201341) and partly supported by the “Qimingxing” Research Fund for Young Talents (HXQMX0083).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical considerations

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

ORCID iD

Hai Yu

Data availability statement

The transcriptomic and single-cell datasets analyzed in this study were obtained from public databases, including PRJNA912889 (NCBI SRA), CRA006645 (CNSA), and GSE227651 (GEO). The original data were generated and published by the respective authors cited in the reference list.

Supplemental material

Supplemental material for this article is available online.

References

GBD 2023 Causes of Death Collaborators. Global burden of 292 causes of death in 204 countries and territories and 660 subnational locations, 1990–2023: a systematic analysis for the Global Burden of Disease Study 2023. Lancet 2025; 406: 1811–1872.

Gallucci

Sperber

Guggisberg

, et al. Post-stroke cognitive impairment remains highly prevalent and disabling despite state-of-the-art stroke treatment. Int J Stroke 2024; 19: 888–897.

Gorelick

Scuteri

Black

, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 2672–2713.

Arai

Can oligodendrocyte precursor cells be a therapeutic target for mitigating cognitive decline in cerebrovascular disease?. J Cereb Blood Flow Metab 2020; 40: 1735–1736.

Liu

Wang

, et al. NG2–glia cell proliferation and differentiation by glial growth factor 2 (GGF2), a strategy to promote functional recovery after ischemic stroke. Biochem Pharmacol 2020; 171: 113720.

Rost

Cougo

Lorenzano

, et al. Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J Cereb Blood Flow Metab 2018; 38: 75–86.

Sasannia

Leigh

Bastani

, et al. Blood–brain barrier breakdown in brain ischemia: insights from MRI perfusion imaging. Neurotherapeutics 2025; 22: e00516.

Yang

Zhan

, et al. The impact of ischemic stroke on gray and white matter injury correlated with motor and cognitive impairments in permanent MCAO rats: a multimodal MRI-based study. Front Neurol 2022; 13: 834329.

Sato

Matsushima

Okumura

, et al. Possible occurrence of delayed leukoencephalopathy following acute ischemic stroke with large-vessel occlusion. Stroke Vasc Interv Neurol 2024; 4: e000995.

10.

Marangon

Castro

ESJH

Cerrato

, et al. Oligodendrocyte progenitors in glial scar: a bet on remyelination. Cells 2024; 13: 1024.

11.

Simons

Gibson

Nave

KA.

Oligodendrocytes: myelination, plasticity, and axonal support. Cold Spring Harb Perspect Biol 2024; 16: a041359.

12.

Levine

Reynolds

Fawcett

JW.

The oligodendrocyte precursor cell in health and disease. Trends Neurosci 2001; 24: 39–47.

13.

Song

Huang

Lin

, et al. Roles of NG2–glia in ischemic stroke. CNS Neurosci Ther 2017; 23: 547–553.

14.

Geng

Zhao

, et al. The NG2–glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke. Neurobiol Dis 2023; 180: 106076.

15.

Zhu

Zuo

Maher

, et al. Olig2-dependent developmental fate switch of NG2 cells. Development 2012; 139: 2299–2307.

16.

Bartus

Burnside

Galino

, et al. ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury. Glia 2019; 67: 1036–1046.

17.

Assinck

Duncan

Plemel

, et al. Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury. J Neurosci 2017; 37: 8635–8654.

18.

Benarroch

What are the roles of oligodendrocyte precursor cells in normal and pathologic conditions?. Neurology 2023; 101: 958–965.

19.

Giacci

Bartlett

Smith

, et al. Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo. J Neurosci 2018; 38: 6491–6504.

20.

Niu

Verkhratsky

Butt

, et al. Demyelination and remyelination: general principles. Adv Neurobiol 2025; 43: 207–255.

21.

Dinkova-Kostova

Abramov

. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 2015; 88: 179–188.

22.

Lin

Mironova

Shrager

, et al. LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair. eLife 2017; 6: e30498.

23.

De Nuccio

Bernardo

Troiano

, et al. NRF2 and PPAR-γ pathways in oligodendrocyte progenitors: focus on ROS protection, mitochondrial biogenesis and promotion of cell differentiation. Int J Mol Sci 2020; 21: 7216.

24.

Lee

Long

Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation. J Clin Invest 2018; 128: 5573–5586.

25.

Sethi

Vidal-Puig

Wnt signalling and the control of cellular metabolism. Biochem J 2010; 427: 1–17.

26.

Martín-Lopez

Mallavibarrena

Villa-Gonzalez

, et al. The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 167270.

27.

Cheng

Wang

Feng

, et al. Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke. Brain 2024; 147: 1294–1311.

28.

Sajad

Zahoor

Rashid

, et al. Pyruvate dehydrogenase-dependent metabolic programming affects the oligodendrocyte maturation and remyelination. Mol Neurobiol 2024; 61: 397–410.

29.

Spaas

van Veggel

Schepers

, et al. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders. Cell Mol Life Sci 2021; 78: 4615–4637.

30.

Roth

Núñez

MT.

Oligodendrocytes: functioning in a delicate balance between high metabolic requirements and oxidative damage. Adv Exp Med Biol 2016; 949: 167–181.

31.

Sánchez-Abarca

Tabernero

Medina

JM.

Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 2001; 36: 321–329.

32.

Zhou

Guan

Jiang

, et al. Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses. CNS Neurosci Ther 2018; 24: 126–134.

33.

Sun

Zhang

Men

, et al. Oligodendrocyte precursor cell-specific blocking of low-glucose-induced activation of AMPK ensures myelination and remyelination. Nat Metab 2025; 7: 2324–2345.

34.

Cui

Yang

, et al. Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation. Cell Death Dis 2024; 15: 350.

35.

Beyer

Fang

Sadrian

, et al. Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 2018; 14: 22–28.

36.

Meyer

Rinholm

JE.

Mitochondria in myelinating oligodendrocytes: slow and out of breath?. Metabolites 2021; 11: 359.

37.

Yazdankhah

Shang

Ghosh

, et al. Modulating EGFR–MTORC1–autophagy as a potential therapy for persistent fetal vasculature (PFV) disease. Autophagy 2020; 16: 1130–1142.

38.

Kim

Bhandari

Brearley

, et al. The inositol phosphate signalling network in physiology and disease. Trends Biochem Sci 2024; 49: 969–985.

39.

Tu-Sekine

Kim

SF.

The inositol phosphate system—a coordinator of metabolic adaptability. Int J Mol Sci 2022; 23: 6747.

40.

Chatree

Thongmaen

Tantivejkul

, et al. Role of inositols and inositol phosphates in energy metabolism. Molecules 2020; 25: 5079.

41.

Xia

Yang

Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations. Cell Res 2005; 15: 83–91.

42.

Mound

Vautrin-Glabik

Foulon

, et al. Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca²⁺ signal. Oncotarget 2017; 8: 72324–72341.

43.

Ding

, et al. Bidirectional regulation of neuronal autophagy in ischemic stroke: mechanisms and therapeutic potential. Ageing Res Rev 2025; 111: 102842.

44.

Miramontes

Czopka

, et al. Synaptic input and Ca²⁺ activity in zebrafish oligodendrocyte precursor cells contribute to myelin sheath formation. Nat Neurosci 2024; 27: 219–231.

45.

Faulkner

Synthesis, function, and regulation of sterol and nonsterol isoprenoids. Front Mol Biosci 2022; 9: 1006822.

46.

Hartmann

Ling

SC.

Central nervous system cholesterol metabolism in health and disease. IUBMB Life 2022; 74: 826–841.

47.

Mojaver

Khazaei

Ahmadpanah

, et al. Dietary intake of coenzyme Q10 reduces oxidative stress in patients with acute ischemic stroke: a double-blind, randomized placebo-controlled study. Neurol Res 2025; 47: 232–241.

48.

Cui

Fang

Kennedy

, et al. Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors. Glia 2014; 62: 1361–1375.

49.

Coppi

Cherchi

Fusco

, et al. Adenosine A(2B) receptors inhibit K⁺ currents and cell differentiation in cultured oligodendrocyte precursor cells and modulate sphingosine-1-phosphate signaling pathway. Biochem Pharmacol 2020; 177: 113956.

50.

Miron

Jung

Kim

, et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008; 63: 61–71.

51.

Huang

Wang

Yang

, et al. Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia. Metabolism 2025; 166: 156161.

52.

Sheth

Iavarone

Liebeskind

, et al. Targeted lipid profiling discovers plasma biomarkers of acute brain injury. PLoS One 2015; 10: e0129735.

53.

Gui

Liu

, et al. Plasma levels of ceramides relate to ischemic stroke risk and clinical severity. Brain Res Bull 2020; 158: 122–127.

54.

Agresti

Meomartini

Amadio

, et al. ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors. Brain Res Rev 2005; 48: 157–165.

55.

Chang

Lim

, et al. TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination. J Cell Biol 2021; 220: e201910213.

56.

Binish

Xiao

Deciphering the role of sphingosine 1-phosphate in central nervous system myelination and repair. J Neurochem 2025; 169: e16228.

57.

Alshehri

Al-Kuraishy

Alsfouk

, et al. The AMPK/GDF15 axis: a novel target for the neuroprotective effects of metformin in ischemic stroke. Mol Neurobiol 2025; 62: 15149–15163.

58.

Jiang

, et al. AMPK: potential therapeutic target for ischemic stroke. Theranostics 2018; 8: 4535–4551.

59.

Palmiero

Pipicelli

Rosa

, et al. Dose-dependent biphasic effect of palmitic acid on oligodendrocyte function: impacts on viability, differentiation, and myelination. J Cell Physiol 2026; 241: e70145.

60.

Scurlock

Dawson

Differential responses of oligodendrocytes to tumor necrosis factor and other pro-apoptotic agents: role of ceramide in apoptosis. J Neurosci Res 1999; 55: 514–522.

61.

Murphy

Lampe

KJ.

Fabricating PLGA microparticles with high loads of the small molecule antioxidant N-acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress. Biotechnol Bioeng 2018; 115: 246–256.

62.

de la Fuente

Queiroz

RML

Ghosh

, et al. Changes in the oligodendrocyte progenitor cell proteome with ageing. Mol Cell Proteomics 2020; 19: 1281–1302.

63.

Sunny

Hammer

Ittermann

, et al. Fetal zone steroids and estrogen show sex specific effects on oligodendrocyte precursor cells in response to oxidative damage. Int J Mol Sci 2021; 22: 6586.

64.

Gao

Liu

Uzoechina

, et al. Oligodendrocyte lineage cells dysfunction in depression: early life stress, adolescent vulnerability and the emerging role of lipid metabolism. Transl Psychiatry 2025; 16: 36.

65.

Miyamoto

Maki

Pham

, et al. Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice. Stroke 2013; 44: 3516–3521.

66.

Marangon

Audano

Pedretti

, et al. Rewiring of glucose and lipid metabolism induced by G protein-coupled receptor 17 silencing enables the transition of oligodendrocyte progenitors to myelinating cells. Cells 2022; 11: 2369.

67.

Zheng

, et al. Metabolic reprogramming of glial cells: fatty acid pathways as regulators of remyelination in multiple sclerosis. Neurobiol Dis 2025; 217: 107179.

68.

Liu

Zhang

, et al. Acute ischemia induces spatially and transcriptionally distinct microglial subclusters. Genome Med 2023; 15: 109.

69.

Han

Zhou

Zhang

, et al. Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain. Sci Transl Med 2024; 16: eadg1323.

70.

Zeng

Cao

Hong

, et al. Single-cell analyses reveal the dynamic functions of Itgb2⁺ microglia subclusters at different stages of cerebral ischemia-reperfusion injury in transient middle cerebral occlusion mice model. Front Immunol 2023; 14: 1114663.

71.

Wang

Liu

, et al. Oligodendrocyte precursor cell transplantation attenuates inflammation after ischemic stroke in mice. Front Neurol 2025; 16: 1583982.

72.

Liu

Jin

Xiao

, et al. Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke. Brain Behav Immun 2019; 82: 13–24.

73.

Strecker

Schmidt-Pogoda

Diederich

, et al. Anti-LINGO-1 treatment restores myelination of corticospinal tract neurons and improves functional recovery after stroke. Brain Pathol 2025; 35: e13280.

74.

Owino

Giddens

Jiang

, et al. GPR37 modulates progenitor cell dynamics in a mouse model of ischemic stroke. Exp Neurol 2021; 342: 113719.

75.

Dai

Chen

, et al. TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia. J Cereb Blood Flow Metab 2020; 40: 639–655.

76.

Shibahara

Nakamura

Wakisaka

, et al. PDGFRβ-positive cell-mediated post-stroke remodeling of fibronectin and laminin α2 for tissue repair and functional recovery. J Cereb Blood Flow Metab 2023; 43: 518–530.

77.

Guan

Guo

, et al. Cerebral ischemic preconditioning aggravates death of oligodendrocytes. Biomolecules 2022; 12: 1872.

78.

Lou

Yang

, et al. Ischemic preconditioning induces oligodendrogenesis in mouse brain: effects of Nrf2 deficiency. Cell Mol Neurobiol 2022; 42: 1859–1873.

79.

Wang

Kang

, et al. Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke. J Cereb Blood Flow Metab 2024; 44: 1487–1500.

80.

Raffaele

Gelosa

Bonfanti

, et al. Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis. Mol Ther 2021; 29: 1439–1458.

81.

Liu

Han

Zheng

, et al. EphA4 regulates white matter remyelination after ischemic stroke through Ephexin-1/RhoA/ROCK signaling pathway. Glia 2022; 70: 1971–1991.

82.

Zhao

Gao

, et al. The Shh/Gli1 signaling pathway regulates regeneration via transcription factor Olig1 expression after focal cerebral ischemia in rats. Neurol Res 2022; 44: 318–330.

83.

Wang

Tang

, et al. Resveratrol-mediated neurorestoration after cerebral ischemic injury—Sonic Hedgehog signaling pathway. Life Sci 2021; 280: 119715.

84.

Choi

Jin

Kim

, et al. High mobility group box 1 as an autocrine chemoattractant for oligodendrocyte lineage cells in white matter stroke. Stroke 2023; 54: 575–586.

85.

Shi

, et al. Oligodendrocyte precursor cells transplantation improves stroke recovery via oligodendrogenesis, neurite growth and synaptogenesis. Aging Dis 2021; 12: 2096–2112.

86.

Tang

Zhong

, et al. Unraveling the complex pathophysiology of white matter hemorrhage in intracerebral stroke: a single-cell RNA sequencing approach. CNS Neurosci Ther 2024; 30: e14652.

87.

Wang

Geng

, et al. Oligodendrocyte precursor cells transplantation protects blood–brain barrier in a mouse model of brain ischemia via Wnt/β-catenin signaling. Cell Death Dis 2020; 11: 9.

88.

Zhuang

Lin

, et al. Buyang Huanwu decoction improves motor function by enhancing internal capsule reorganization through inhibiting Notch signaling after ischemic stroke. J Ethnopharmacol 2025; 348: 119812.

89.

Chen

Zhang

, et al. Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 2018; 371: 229–241.

90.

Sun

Fang

Ren

, et al. WIN55,212-2 protects oligodendrocyte precursor cells in stroke penumbra following permanent focal cerebral ischemia in rats. Acta Pharmacol Sin 2013; 34: 119–128.

91.

Sun

Fang

Chen

, et al. WIN55, 212-2 promotes differentiation of oligodendrocyte precursor cells and improve remyelination through regulation of the phosphorylation level of the ERK 1/2 via cannabinoid receptor 1 after stroke-induced demyelination. Brain Res 2013; 1491: 225–235.

92.

Liu

Song

, et al. M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice. Theranostics 2022; 12: 3553–3573.

93.

Zhang

, et al. TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair. J Neuroinflammation 2023; 20: 50.

94.

Zhang

, et al. Poststroke intravenous transplantation of human mesenchymal stem cells improves brain repair dynamics and functional outcomes in aged mice. Stroke 2023; 54: 1088–1098.

95.

Zarriello

Neal

Kaneko

, et al. T-regulatory cells confer increased myelination and stem cell activity after stroke-induced white matter injury. J Clin Med 2019; 8: 537.

96.

Shen

Chen

, et al. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 2007; 27: 6–13.

97.

Zhang

Wang

Zhang

, et al. Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke. Exp Neurol 2015; 272: 170–180.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.46 MB

0.00 MB