JOURNAL/mgres/04.03/01612956-202612000-00001/figure1/v/2026-07-23T200825Z/r/image-tiff Defects in myelination impair nerve impulse conduction and functional connectivity, which could lead to cognitive, behavioral and motor deficits in various neurological disorders. Adequate oxygen delivery is vital for brain development, while hypoxia in newborns tends to result in developmental deficiencies in myelination of the brain. The disruption of oligodendrocytes and their progenitor cells caused by hypoxia has been well researched. Nonetheless, the impairing dynamic myelination process is still unclear. Utilizing zebrafish as a model, we established hypoxia via cobalt chloride exposure or low oxygen (8%) incubation. Hypoxia significantly reduced oligodendrocyte progenitor cell numbers in the dorsal spinal cord, impaired migration velocity and suppressed proliferation. Myelination deficits were evident through decreased myelin sheath segment intensity in Tg(MBP:eGFP-CAAX) larvae. Time-lapse imaging revealed compromised dynamic myelination by individual oligodendrocytes under hypoxia, with fewer sheaths and reduced extension rates. Mechanistically, hypoxia elevated reactive oxygen species levels and disrupted mitochondrial membrane potential in cultured rat oligodendrocyte progenitor cells. Nanoscale magnesium hydride, a hydrogen-releasing agent, attenuated these effects. In vivo , magnesium hydride treatment rescued oligodendrocyte progenitor cell numbers and enhanced myelinogenesis capacity in hypoxic zebrafish. These findings demonstrate that magnesium hydride mitigates hypoxia-induced oxidative stress and mitochondrial dysfunction, thereby alleviating myelination deficits.

Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the “microglial lineage,” which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.

Insufficient maturation of oligodendrocyte progenitor cells (OPCs) contributes to the failure of endogenous remyelination in multiple sclerosis (MS). It remains unclear whether dysregulated oligodendroglial microRNAs (miRNAs) impede remyelination in chronic MS lesions. In this study, we demonstrated that miR-126a-3p was enriched in oligodendroglia from chronic inactive MS plaques and chronic lesions in mice with experimental autoimmune encephalomyelitis (EAE). Functional analyses revealed that miR-126a-3p inhibited OPC differentiation in vitro and that the specific deletion of miR-126a-3p in oligodendroglia accelerated the remyelination process in the EAE and lysolecithin-induced demyelination models. Mechanistically, miR-126a-3p exerted an inhibitory effect on OPC differentiation and remyelination by directly targeting peroxin-5 (Pex5) transcripts. A screening of a US Food and Drug Administration-approved drug library based on Pex5 levels led to the identification of ganciclovir, an antiviral agent, as a potent proremyelinating agent after in vivo demyelinating events. These results identify the aberrant miR-126a-3p-Pex5 axis in oligodendroglia as a potential therapeutic target to facilitate remyelination in chronic MS lesions.

Myelin, a multilamellar membrane structure enwrapping axons, is essential for rapid saltatory conduction, metabolic support, and long-term axonal integrity in the central nervous system (CNS). Myelination by oligodendrocytes (OLs) constitutes a highly dynamic and orchestrated process, encompassing distinct stages: target axon recognition, axonal wrapping, membrane expansion, and compaction. This review comprehensively summarizes recent advances in understanding the dynamics of CNS myelination which is spatiotemporally regulated through a complex interplay of membrane protein interaction, neuronal activity, metabolic checkpoints, and mechanosensory mechanisms. We highlight how adhesive molecules, cytoskeletal dynamics, and polarized membrane trafficking collectively drive the precise spiraling of myelin around axons. Furthermore, we emphasize the indispensable non-cell autonomous roles of astrocytes and microglia, which contribute critically through lipid transfer, phagocytic refinement, and modulation of the extracellular matrix. Beyond development, we discuss mechanisms that sustain myelin homeostasis, such as autophagy-lysosomal clearance. By integrating these mechanistic insights, we not only underscore the exquisite precision of CNS myelination but also illuminate potential therapeutic targets for demyelinating disorders.

Once viewed as a homogenous population, microglia are now understood to exist as a dynamic continuum of functionally distinct states whose existence is supported by accumulating evidence from multiple experimental approaches. This heterogeneity, spanning molecular, morphological, and metabolic dimensions, is actively sculpted by brain region, life stage, and a complex microenvironment of neuronal, astrocytic, and systemic signals. In neurological disorders such as Alzheimer’s disease, this plasticity leads to context-dependent diversification into discrete subsets—ranging from protective, phagocytic phenotypes to detrimental, inflammatory ones—that critically influence disease progression. Decoding this heterogeneity through single-cell and spatial omics provides a new pharmacological blueprint: it reveals key druggable nodes (e.g., TREM2, CD14) that govern pathogenic state transitions and informs the rational design of subset-selective delivery systems (e.g., ligand-directed nanocarriers). However, translating these insights requires overcoming persistent challenges, including species differences between mouse and human microglia, a lack of tools for causal subset manipulation, and the integration of spatial with temporal dynamics. By framing microglial heterogeneity as a central targetable axis, this review outlines a pathway for developing precise, state-modulating therapeutics to intervene in neurodegeneration and neuroinflammation.

Central nervous system (CNS) injuries trigger a complex glial response, in which oligodendrocyte precursor cells (OPCs) play a far more dynamic role than previously recognized. Moving beyond their canonical function as a remyelination reservoir, reactive OPCs emerge as plastic signaling hubs whose fate and function are dictated by injury-specific cues. This review synthesizes recent evidence to propose a novel conceptual framework: the "reactive OPC state code." We argue that deciphering this code-the molecular signatures that define pro-regenerative, immunomodulatory, or maladaptive OPC states-is the key to understanding functional heterogeneity in CNS injury. We critically analyze how distinct pathological contexts (trauma, ischemia, neuroinflammation) rewrite this code, leading to diverse outcomes. Finally, we pivot from a generic discussion of OPC-directed therapies to advocate for "state-specific targeting" as the next frontier in translational medicine, offering a roadmap for developing precision interventions that steer reactive OPCs towards repair. This perspective aims to redefine OPC reactivity from a passive response to a central, druggable axis in CNS pathology and repair.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), execute essential functions in neural development, homeostasis, and repair. However, their persistent or dysregulated activation is a hallmark of diverse neurological disorders, where they transition from protective sentinels to drivers of chronic neuroinflammation and tissue damage. This duality has spurred the development of therapeutic strategies aimed not merely at suppressing microglial activity, but at fundamentally resetting the CNS immune landscape. Here, we review the paradigm of transient microglial depletion followed by endogenous repopulation, a strategy that effectively replaces a dysfunctional or pathologically primed microglial compartment with a rejuvenated cohort. Emerging evidence demonstrates that repopulated microglia exhibit a distinct phenotype-characterized by attenuated inflammatory profiles, upregulated homeostatic and neurotrophic gene expression, and enhanced phagocytic capacity-thereby conferring neuroprotection and promoting functional recovery across preclinical models of acute injury, neurodegeneration, and demyelinating disease. We critically evaluate the pharmacological and genetic tools used to achieve depletion, synthesize the context-dependent outcomes across disease spectra, and discuss the mechanistic basis for the superior therapeutic profile of the repopulation phase. Finally, we address the key translational challenges-including therapeutic windows, age- and sex-dependent effects, and the gap between rodent models and human biology-that must be overcome to transform this innovative strategy from a powerful experimental tool into a viable clinical modality for reprogramming CNS immunity.

Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) formed by aggregates of hyperphosphorylated tau proteins. It presents a formidable global health challenge, prompting the exploration of innovative therapeutic strategies. This review aims to provide a thorough discussion of astrocytes and microglia to examine whether they are overall beneficial or detrimental for AD on the global level. Based on this, this review describes the treatment solutions that are likely to entail the manipulation of glial cells to reduce inflammation, opting to boost clearance of toxic proteins, thus stabilizing the effects of AD. These glial entities, inherent to the central nervous system, extend their functions beyond structural support, actively engaging in various physiological and pathological processes associated with AD. Both astroglia and microglia contribute significantly to the neuroinflammatory response observed in AD. Reactive astrocytes release inflammatory mediators, while activated microglia release cytokines, chemokines, and reactive oxygen species, collectively assisting a chronic state of neuroinflammation. Additionally, astrocytes partake in the clearance of Aβ, while microglia play a pivotal role in phagocytosing Aβ plaques. In AD, ongoing inflammation may cause a buildup of Aβ, which causes problems with the functions of astroglia and microglia and also worsens these issues with communication between neurons, a key factor in cognitive decline. In addition, there are tremendous opportunities to identify new biomarkers specific to glial disorders, genomic and epigenomic approaches for the selection of patients, using multimodal imaging techniques, and the application of machine learning algorithms in the future for personalized glial-targeted therapies.

Myelin is the lipid-rich insulating layer that wraps axons, providing trophic support and ensuring rapid propagation of the electrical impulses that underlie nervous system function. In the CNS, myelin is produced by mature oligodendrocytes (OLs) that arise from oligodendrocyte precursor cells (OPCs). Myelination is regulated by a variety of molecules, including growth factors, hormones, and extracellular molecules, which activate signaling cascades that drive cellular maturation. Key signaling molecules and downstream pathways that control myelination have been identified in cell culture and rodent models. Although much is known about the development of OL and its progenitor cell in vitro and in vivo, how CNS myelin is dynamically formed through OL processes is still unclear. Zebrafish share significant genetic and physiological similarities with mammals, including humans, making them a relevant model for studying complex biological processes like myelination. Due to its transparent larval development, zebrafish facilitates live imaging studies, enabling dynamic visualizations of cellular and molecular processes in real-time studies. In this chapter, we reviewed the latest insights into OL development and myelin formation, with a particular emphasis on the mechanisms regulating dynamic myelination in zebrafish. We highlight the dynamic extension and retraction of myelin sheath segments and the role of neuronal activity in regulating the developmental myelination in zebrafish. In addition, we also discussed the mechanisms of Ranvier node positioning and axon targeting of myelin sheaths in the spinal cord of zebrafish larvae. Finally, we reviewed the recent progress of zebrafish as a demyelinating disease model for drug discovery of pharmacological compounds favoring myelin regeneration.

The primary culture of oligodendrocyte progenitor cells (OPCs) provides an indispensable tool for characterizing their biological properties and myelin repair potential. However, the current OPC preparation methods are mainly limited to rat tissues, and it remains a substantial challenge for replicating the primary culture from mouse tissues to generate large quantities of high-quality OPCs. Here, we describe a protocol to successfully establish highly enriched OPC cultures from the cerebral cortex of mice at the age of neonatal 3 days. OPCs were isolated and purified from the bed layer of astrocytes by shaking for 6 h at 250 rpm. Using this protocol, mouse OPCs can be easily produced in bulk and economically without the need for specific cell-surface antibodies and equipment. These mouse OPC cultures were identified by immunocytochemical, immunobloting and RNA-seq analysis. Furthermore, they could be expanded in vitro and differentiate into mature oligodendrocytes. We propose this method as a viable and affordable protocol to obtain mouse OPC culture, which should significantly facilitate studies on OPC lineage progression and their application in myelin-related disease modeling and regenerative medicine.

Axon-wrapping myelin sheaths formed by oligodendrocytes are essential for proper functions of the central nervous system. Although much is known about oligodendrocyte development, how the myelin dynamically forms remains unclear. Here we show the preferentially unidirectional extension of developing myelin mediated by Wnt gradient and required for proper axon functions. Using larval zebrafish as an in vivo model, we found that developing myelin in the spinal cord preferentially extends to the anterior end, and this process is dependent on an anterior-to-posterior Wnt4b gradient. Taking advantage of the large size of Mauthner-cell axons, we further showed that disruption of this directional extension impairs the even length distribution of myelin sheaths and faithful transduction of action potentials along the axon, and reduces the reliability of escape behavior. Thus, our study reveals a novel process for precise regulation of myelination, providing a new insight into myelin structuring and functioning. ### Competing Interest Statement The authors have declared no competing interest. Ministry of Science and Technology of the People's Republic of China STI2030-Major Projects, 2022ZD0204700 National Natural Science Foundation of China, 31400920, 31871026 National Key Research and Development Program of China, 2016YFA0100802 Shanghai Municipal Science and Technology Major Project, 18JC1410100, 2018SHZDZX05 Key Research Program of Frontier Sciences of Chinese Academy of Sciences, QYZDY-SSW-SMC028 Strategic Priority Research Program of Chinese Academy of Sciences, XDB32010200

The axon-wrapping myelin sheath is essential for CNS function. Myelination defects occur in various neurodevelopmental disorders, but the underlying mechanism remains poorly understood. Human solute carrier 44A1 (SLC44A1) deficiency causes a new type of childhood-onset neurodegeneration with cerebellar atrophy and leukoencephalopathy that lacks effective treatment. Here, we show that SLC44A1 is enriched in oligodendrocytes and is required for myelin development in the CNS of zebrafish and rodents. In vivo time-lapse imaging of Slc44a1b-deficient zebrafish reveals impaired oligodendroglial maturation and myelinogenesis. Mechanistically, SLC44A1 deficiency disrupts the expression of genes involved in the phosphatidylcholine production pathway and subsequently inhibits phospholipid biosynthesis and disturbs the lipid composition of myelin sheaths. More importantly, supplementation with citicoline, a natural choline metabolite, restores developmental myelination in SLC44A1-deficient animals. Our findings demonstrate that SLC44A1 is essential for CNS myelination, and citicoline supplementation represents a potential therapy for developmental hypomyelination.

Rationale: As a highly plastic population, parenchymal astrocytes have demonstrated the capacity to become activated and recapitulate neurogenic potential in response to traumatic central nervous system (CNS) injuries, representing a latent reservoir for neuronal regeneration in non-neurogenic brain regions. However, the extrinsic and intrinsic factors regulating this process remain poorly characterized. Elucidating these molecular mechanisms is crucial to harnessing the regenerative potential of reactive astrocytes in CNS repair. Methods: A multidisciplinary approach combining immunostaining, western blotting, RNA interference (RNAi), gene knock out and fate-mapping was used to investigate the role of topoisomerase IIα (TOP2a) in regulation of the stemness response in reactive astrocytes to traumatic brain injury (TBI). Results: Both in vitro and in vivo analyses demonstrated that TBI induces a stem cell-like response in reactive astrocytes concomitant with TOP2a upregulation. Pharmacological inhibition or genetic deletion of TOP2a significantly attenuated this stemness response. Neurosphere culture assay indicates that TOP2a might act as a downstream factor of Sonic Hedgehog (SHH) signaling to mediate the acquisition of stem cell potential. Conclusions: This study identifies TOP2a as a pivotal intrinsic regulator of astrocytic stem cell potential in the injured brain, which will advance our understanding of the molecular underpinnings of the stem cell response and its therapeutic application in neural regeneration.

Oligodendrocyte precursor cells (OPCs) are recognized as the progenitors responsible for the generation of oligodendrocytes, which play a critical role in myelination of central nervous system. In addition, in demyelinating diseases, such as brain trauma, ischemia, and multiple sclerosis, OPCs are also found in demyelinated regions, but fail to differentiate into mature oligodendrocytes and remyelinate. From traditional view, OPC is victim of immune response. However, recent studies have shed light on immune associated OPCs (imOPCs), which are induced by interferon γ (IFN-γ), and interleukin 17 (IL-17), and are involved in the innate and adaptive immune activation. By expressing multiple natural immune pattern recognition receptors, such as Toll-like receptors, imOPCs can phagocytose myelin debris for antigen presentation. Furthermore, imOPCs can also secrete various inflammatory and chemotactic factors to regulate the differentiation of Th0 cells and the recruitment of NK cells, granulocytes and macrophages. Thus, it is of great importance to explore the immunoregulatory function of OPCs to elucidate the mechanisms and treatments of demyelinating diseases.

Correlation analysis of the TNFRSF19 and the Wnt/β-catenin signaling pathway target gene expression levels in smoker non-small cell lung cancer patients based on GEO database.

The TNFRSF19 within 13q12.12 risk chromatin region functions as a lung cancer suppressor by binding Wnt3a to inhibit Wnt/β-catenin signaling.

Abstract Cancer risk loci provide special clues for uncovering pathogenesis of cancers. The TNFRSF19 gene located within the 13q12.12 lung cancer risk locus encodes TNF receptor superfamily member 19 (TNFRSF19) protein and has been proved to be a key target gene of a lung tissue–specific tumor suppressive enhancer, but its functional role in lung cancer pathogenesis remains to be elucidated. Here we showed that the TNFRSF19 gene could protect human bronchial epithelial Beas-2B cells from pulmonary carcinogen nicotine-derived nitrosamine ketone (NNK)-induced malignant transformation. Knockout of the TNFRSF19 significantly increased NNK-induced colony formation rate on soft agar. Moreover, TNFRSF19 expression was significantly reduced in lung cancer tissues and cell lines. Restoration of TNFRSF19 expression in A549 lung cancer cell line dramatically suppressed the tumor formation in xenograft mouse model. Interestingly, the TNFRSF19 protein that is an orphan membrane receptor could compete with LRP6 to bind Wnt3a, thereby inhibiting the Wnt/β-catenin signaling pathway that is required for NNK-induced malignant transformation as indicated by protein pulldown, site mutation, and fluorescence energy resonance transfer experiments. Knockout of the TNFRSF19 enhanced LRP6–Wnt3a interaction, promoting β-catenin nucleus translocation and the downstream target gene expression, and thus sensitized the cells to NNK carcinogen. In conclusion, our study demonstrated that the TNFRSF19 inhibited lung cancer carcinogenesis by competing with LRP6 to combine with Wnt3a to inhibit the Wnt/β-catenin signaling pathway. Implications: These findings revealed a novel anti-lung cancer mechanism, highlighting the special significance of TNFRSF19 gene within the 13q12.12 risk locus in lung cancer pathogenesis.

In the mammalian central nervous system (CNS), astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics. These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological, molecular, and functional changes to adopt so-called ‘reactive’ states in response to CNS injury or disease. In recent years, interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances. Here, we will review and discuss the well-established and emerging astroglial biology and functions, with emphasis on their potential as therapeutic targets for CNS injury, including traumatic and ischemic injury. This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.