Myelin-forming Cells Research Articles

Myelinated fibers of the mouse spinal cord after a 30-day space flight.

Myelinated fibers and myelin-forming cells in the spinal cord at the L3-L5 level were studied in C57BL/6N mice that had spent 30 days in space. Signs of destruction of myelin in different areas of white matter, reduction of the thickness of myelin sheath and axon diameter, decreased number of myelin-forming cells were detected in "flight" mice. The stay of mice in space during 30 days had a negative impact on the structure of myelinated fibers and caused reduced expression of the markers myelin-forming cells. These findings can complement the pathogenetic picture of the development of hypogravity motor syndrome.

Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes.

Leukodystrophies are hereditary central white matter disorders caused by oligodendrocyte dysfunction. Recent clinical trials for some of these devastating neurological conditions have employed an ex vivo gene therapy approach that showed improved endpoints because cross-correction of affected myelin-forming cells occurred following secretion of therapeutic proteins by transduced autologous grafts. However, direct gene transfer to oligodendrocytes is required for the majority of leukodystrophies with underlying mutations in genes encoding non-secreted oligodendroglial proteins. Recombinant adeno-associated viral (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in rodents have shown that the use of cellular promoters is sufficient to target AAV-mediated transgene expression to glia. The potential of this strategy has not been exploited. The major caveat of the AAV system is its limited packaging capacity of ~5 kb, providing the rationale for identifying small yet selective recombinant promoters. Here, we characterize the human myelin associated glycoprotein (MAG) promoter for reliable targeting of AAV-mediated transgene expression to oligodendrocytes in vivo. A homology screen revealed highly conserved genomic regions among mammalian species upstream of the transcription start site. Recombinant AAV expression cassettes carrying the cDNA encoding enhanced green fluorescent protein (GFP) driven by truncated versions of the recombinant MAG promoter (2.2, 1.5 and 0.3 kb in size) were packaged as cy5 vectors and delivered into the dorsal striatum of mice. At 3 weeks post-injection, oligodendrocytes, neurons and astrocytes expressing the reporter were quantified by immunohistochemical staining. Our results revealed that both 2.2 and 1.5 kb MAG promoters targeted more than 95% of transgene expression to oligodendrocytes. Even the short 0.3 kb fragment conveyed high oligodendroglial specific transgene expression (>90%) in vivo. Moreover, cy5-MAG2.2-GFP delivery to the neonate CNS resulted in selective GFP expression in oligodendrocytes for at least 8 months. Broadly, the characterization of the extremely short yet oligodendrocyte-specific human MAG promoter may facilitate modeling neurological diseases caused by oligodendrocyte pathology and has translational relevance for leukodystrophy gene therapy.

The Role of 3-O-Sulfogalactosylceramide, Sulfatide, in the Lateral Organization of Myelin Membrane.

Sulfatide (3-O-sulfogalactosylceramide, SM4s) was isolated by Thudichum from the human brain in 1884. Together with galactosylceramide, its direct metabolic precursor in the biosynthetic pathway, sulfatide is highly enriched in myelin in the central and peripheral nervous system, and it has been implicated in several aspects of the biology of myelin-forming cells. Studies obtained using galactolipid-deficient mice strongly support the notion that sulfatide plays critical roles in the correct structure and function of myelin membrane. A number of papers are suggesting that these roles are mediated by a specific function of sulfatide in the lateral organization of myelin membrane, thus affecting the sorting, lateral assembly, membrane dynamics and also the function of specific myelin proteins in different substructures of the myelin sheath. The consequences of altered sulfatide metabolism and sulfatide-mediated myelin organization with respect to myelin diseases are still poorly understood, but it's very likely that sulfatide might represent not only a critical player in the pathogenesis of several diseases, including multiple sclerosis and Alzheimer's disease, but also a potentially promising therapeutic target.

Krabbe disease: involvement of connexin43 in the apoptotic effects of sphingolipid psychosine on mouse oligodendrocyte precursors.

Krabbe disease is a genetic demyelinating syndrome characterized by deficiency of the enzyme β-galactosylceramidase, lysosomal psychosine accumulation, and loss of myelin-forming cells. In this study, some apoptotic markers such as apoptotic index (AI), DNA fragmentation, caspase-3, PTEN, Bad, and PI3K were determined in oligodendrocyte precursors from wild type or twitcher mice untreated or treated with psychosine. Twitcher is a natural mouse model of Krabbe disease containing a premature stop codon (W339X) in the β-galactosylceramidase gene. Moreover, a possible involvement of connexin (Cx)43 in cell death of oligodendrocyte precursors induced by psychosine was investigated with the final aim to provide a contribution to the knowledge of the molecular mechanisms and pathophysiological events that occur in Krabbe disease. Connexins are a multigene family of structurally related trans-membrane proteins able to modulate essential cellular processes such as proliferation, differentiation and migration. Among these, Cx43 is the predominant isoform in many cell types, including neural progenitor cells. Our results showed an increase of AI, DNA fragmentation, caspase-3, PTEN, Bad, and Cx43 associated to a decrease of PI3K, pAKT and pBad. Taken together, these findings suggest an involvement of Cx43 in the psychosine-mediated apoptosis of primary oligodendrocyte progenitors from wild type or twitcher mice, used for the first time as cell models in comparison. It could open unexplored perspective also for other demyelinating diseases.

Alterations in hippocampal myelin and oligodendrocyte precursor cells during epileptogenesis

Recent reports have described damage to myelinated fibers in the central nervous system (CNS) in patients with temporal lobe epilepsy (TLE) and animal models. However, only limited data are available on the dynamic changes that occur in myelinated fibers, oligodendrocytes (which are myelin-forming cells), and oligodendrocyte precursor cells (OPCs), which are a reservoir of new oligodendrocytes, in the hippocampus throughout epileptogenesis. The current study was designed to examine this issue using a rat model of lithium-pilocarpine-induced epilepsy. Electroencephalography (EEG), immunofluorescence, and Western blot analysis showed that the loss of myelin and oligodendrocytes in the rat hippocampus began during the acute stage of epileptogenesis, and the severity of this loss increased throughout epileptogenesis. Accompanying this loss of myelin and oligodendrocytes, OPCs in the rat hippocampus became activated and their populations increased during several phases of epileptogenesis (the acute, latent and chronic phases). The transcription factors olig1 and olig2, which play crucial roles in regulating OPC proliferation, differentiation and remyelination, were up-regulated during the early phases (the acute and latent phases) followed by a sharp decline in their expression during the chronic and late chronic phases.This study is the first to confirm the loss of myelin and oligodendrocytes during lithium-pilocarpine-induced epileptogenesis accompanied by a transient increase in the number of OPCs. Prevention of the loss of myelin and oligodendrocytes may provide a novel treatment strategy for epilepsy.

Nicotinic acetylcholine receptors mediate donepezil-induced oligodendrocyte differentiation.

Oligodendrocytes are the myelin-forming cells of the central nervous system (CNS). Failure of myelin development and oligodendrocyte loss results in serious human disorders, including multiple sclerosis. Here, we show that donepezil, an acetlycholinesterase inhibitor developed for the treatment of Alzheimer's disease, can stimulate oligodendrocyte differentiation and maturation of neural stem cell-derived oligodendrocyte progenitor cells without affecting proliferation or cell viability. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase, and MOG, in addition to transcription factors that regulate oligodendrocyte differentiation and myelination, were rapidly increased after treatment with donepezil. Furthermore, luciferase assays confirmed that both MAG and MBP promoters display increased activity upon donepezil-induced oligodendrocytes differentiation, suggesting that donepezil increases myelin gene expression mainly through enhanced transcription. We also found that the increase in the number of oligodendrocytes observed following donepezil treatment was significantly inhibited by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine, but not by the muscarinic acetylcholine receptor antagonist scopolamine. Moreover, donepezil-induced myelin-related gene expression was suppressed by mecamylamine at both the mRNA and protein level. These results suggest that donepezil stimulates oligodendrocyte differentiation and myelin-related gene expression via nAChRs in neural stem cell-derived oligodendrocyte progenitor cells. We show that donepezil, a drug for the treatment of Alzheimer disease, can stimulate oligodendrocyte differentiation and maturation of oligodendrocyte progenitor cells. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase and MOG in addition to transcripton factors that regulate oligodendrocyte differentiation and myelination were rapidly increased after treatment with donepezil. These effects were partly dependent on nicotinic acetylcholine receptor (nAChR).

ADNP/ADNP2 expression in oligodendrocytes: implication for myelin-related neurodevelopment.

Oligodendrocytes, the myelin-forming cells of the central nervous system, play important roles in brain development and maintenance. Activity-dependent neuroprotective protein (ADNP), an early marker essential for brain formation, interacts with microtubule end-binding proteins (EB1, EB2, and EB3). EB1 and EB3 are highly expressed in neurons (axons and dendritic spines, respectively) and EB1 enhancement of neurite outgrowth is attenuated by EB2. ADNP/EB presence in oligodendrocytes has not been studied so far. Here, we measured messenger RNA (mRNA) levels of ADNP and EB1-EB3 in rat brain oligodendrocytes during culture maturation and in rat brains during development (1, 35, and 75days) in comparison with rat astrocytes, dorsal root ganglion (DRG) neurons, and the oligodendroglia cell lines (OLN-93 cell line, not expressing the microtubule-associated protein (MAP) tau, and OLN-93 cells stably transfected to express various forms of tau). Results showed that all transcripts studied were expressed in oligodendrocytes. ADNP and EB2 mRNA transcript content peaked at the time of oligodendrocyte maturation (5days in vitro) and was highest in newborn rat brains compared with mature brains. ADNP2 (the only family member of ADNP), and EB1, although expressed in lower quantities, essentially paralleled ADNP and EB2 expression patterns, respectively. EB3 mRNA, peaking upon oligodendrocyte maturation, showed an apparent second peak of expression (10days in vitro) and increased in the mature rat brain compared with the newborn brain. DRG cells expressed the highest levels of EB3, when compared with oligodendrocyte precursors and with astrocytes but not when compared with mature oligodendrocytes. Mature oligodendrocytes and oligodendrocyte precursors expressed ~30-40-fold more EB2 vs. EB3, and ~4-7-fold vs. ADNP. DRGs expressed ~5-fold more EB2 vs. EB3 and astrocytes showed an in-between (~20-fold) ratio. Only DRGs expressed similar EB1 and EB3 transcript levels, contrasting with oligodendrocyte and astrocytes (~10-30-fold more EB1). Astrocytes expressed more ADNP than DRGs and oligodendrocyte precursor cells (~2-fold) but not compared with mature oligodendrocytes. EB1 and EB3 were previously found to be associated with tau. Immortalized oligodendrocytes showed an intermediate phenotype of mRNA expression compared with oligodendrocyte precursor cells and mature oligodendrocytes with tau transfection reducing overall ADNP and EB expression. In summary, ADNPs and EBs are highly expressed in oligodendrocytes suggesting an impact on myelin formation in health and disease.

Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons.

The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long-standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination.

Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination.

ABSTRACTClostridium perfringens epsilon toxin (ε-toxin) is responsible for a devastating multifocal central nervous system (CNS) white matter disease in ruminant animals. The mechanism by which ε-toxin causes white matter damage is poorly understood. In this study, we sought to determine the molecular and cellular mechanisms by which ε-toxin causes pathological changes to white matter. In primary CNS cultures, ε-toxin binds to and kills oligodendrocytes but not astrocytes, microglia, or neurons. In cerebellar organotypic culture, ε-toxin induces demyelination, which occurs in a time- and dose-dependent manner, while preserving neurons, astrocytes, and microglia. ε-Toxin specificity for oligodendrocytes was confirmed using enriched glial culture. Sensitivity to ε-toxin is developmentally regulated, as only mature oligodendrocytes are susceptible to ε-toxin; oligodendrocyte progenitor cells are not. ε-Toxin sensitivity is also dependent on oligodendrocyte expression of the proteolipid myelin and lymphocyte protein (MAL), as MAL-deficient oligodendrocytes are insensitive to ε-toxin. In addition, ε-toxin binding to white matter follows the spatial and temporal pattern of MAL expression. A neutralizing antibody against ε-toxin inhibits oligodendrocyte death and demyelination. This study provides several novel insights into the action of ε-toxin in the CNS. (i) ε-Toxin causes selective oligodendrocyte death while preserving all other neural elements. (ii) ε-Toxin-mediated oligodendrocyte death is a cell autonomous effect. (iii) The effects of ε-toxin on the oligodendrocyte lineage are restricted to mature oligodendrocytes. (iv) Expression of the developmentally regulated proteolipid MAL is required for the cytotoxic effects. (v) The cytotoxic effects of ε-toxin can be abrogated by an ε-toxin neutralizing antibody.

Donor mesenchymal stem cell-derived neural-like cells transdifferentiate into myelin-forming cells and promote axon regeneration in rat spinal cord transection.

IntroductionSevere spinal cord injury often causes temporary or permanent damages in strength, sensation, or autonomic functions below the site of the injury. So far, there is still no effective treatment for spinal cord injury. Mesenchymal stem cells (MSCs) have been used to repair injured spinal cord as an effective strategy. However, the low neural differentiation frequency of MSCs has limited its application. The present study attempted to explore whether the grafted MSC-derived neural-like cells in a gelatin sponge (GS) scaffold could maintain neural features or transdifferentiate into myelin-forming cells in the transected spinal cord.MethodsWe constructed an engineered tissue by co-seeding of MSCs with genetically enhanced expression of neurotrophin-3 (NT-3) and its high-affinity receptor tropomyosin receptor kinase C (TrkC) separately into a three-dimensional GS scaffold to promote the MSCs differentiating into neural-like cells and transplanted it into the gap of a completely transected rat spinal cord. The rats received extensive post-operation care, including cyclosporin A administrated once daily for 2 months.ResultsMSCs modified genetically could differentiate into neural-like cells in the MN + MT (NT-3-MSCs + TrKC-MSCs) group 14 days after culture in the GS scaffold. However, after the MSC-derived neural-like cells were transplanted into the injury site of spinal cord, some of them appeared to lose the neural phenotypes and instead transdifferentiated into myelin-forming cells at 8 weeks. In the latter, the MSC-derived myelin-forming cells established myelin sheaths associated with the host regenerating axons. And the injured host neurons were rescued, and axon regeneration was induced by grafted MSCs modified genetically. In addition, the cortical motor evoked potential and hindlimb locomotion were significantly ameliorated in the rat spinal cord transected in the MN + MT group compared with the GS and MSC groups.ConclusionGrafted MSC-derived neural-like cells in the GS scaffold can transdifferentiate into myelin-forming cells in the completely transected rat spinal cord.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0100-7) contains supplementary material, which is available to authorized users.

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics.

The polarity protein Scribble regulates myelination and remyelination in the central nervous system.

The development and regeneration of myelin by oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), requires profound changes in cell shape that lead to myelin sheath initiation and formation. Here, we demonstrate a requirement for the basal polarity complex protein Scribble in CNS myelination and remyelination. Scribble is expressed throughout oligodendroglial development and is up-regulated in mature oligodendrocytes where it is localised to both developing and mature CNS myelin sheaths. Knockdown of Scribble expression in cultured oligodendroglia results in disrupted morphology and myelination initiation. When Scribble expression is conditionally eliminated in the myelinating glia of transgenic mice, myelin initiation in CNS is disrupted, both during development and following focal demyelination, and longitudinal extension of the myelin sheath is disrupted. At later stages of myelination, Scribble acts to negatively regulate myelin thickness whilst suppressing the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAP) kinase pathway, and localises to non-compact myelin flanking the node of Ranvier where it is required for paranodal axo-glial adhesion. These findings demonstrate an essential role for the evolutionarily-conserved regulators of intracellular polarity in myelination and remyelination.

Deletion of Jun proteins in adult oligodendrocytes does not perturb cell survival, or myelin maintenance in vivo.

Oligodendrocytes, the myelin-forming glial cells of the central nervous system (CNS), are fundamental players in rapid impulse conduction and normal axonal functions. JunB and c-Jun are DNA-binding components of the AP-1 transcription factor, which is known to regulate different processes such as proliferation, differentiation, stress responses and death in several cell types, including cultured oligodendrocyte/lineage cells. By selectively inactivating Jun B and c-Jun in myelinating oligodendrocytes in vivo, we generated mutant mice that developed normally, and within more than 12 months showed normal ageing and survival rates. In the adult CNS, absence of JunB and c-Jun from mature oligodendrocytes caused low-grade glial activation without overt signs of demyelination or secondary leukocyte infiltration into the brain. Even after exposure to toxic or autoimmune oligodendrocyte insults, signs of altered oligodendrocyte viability were mild and detectable only upon cuprizone treatment. We conclude that JunB and c-Jun expression in post-mitotic oligodendrocytes is mostly dispensable for the maintainance of white matter tracts throughout adult life, even under demyelinating conditions.

Functional regeneration of the brain: white matter matters.

Functional regeneration of the brain: white matter matters.

Role of myelin sheath energy metabolism in neurodegenerative diseases.

More than any other organs, brain energy demand is entirely dependent on glucose catabolism through the oxidative phosphorylation (OXPHOS). Glucose is the major cerebral energy substrate in the nervous system (NS). Ketone bodies can be utilized as an additional substrate, but in any case, neurons critically depend on oxygen supply. This sounds quite surprising considering that NS contains few mitochondria, which are universally considered the exclusive site of OXPHOS. Several authors have hypothesized that glia may be involved in the energetic support of the axon, supposing an unknown trophic role played by myelin sheath. In fact, the myelin-forming cells, i.e., oligodendrocytes and Schwann cells in central and peripheral NS, respectively, appear fundamental for the maintenance of long-term axonal functional integrity (Lee et al., 2012).

Perspectives on neuroreparative therapies for treating multiple sclerosis.

A need to develop neuroreparative therapies for multiple sclerosis (MS): MS is the most common neurological disease of young Caucasian adults. This disease is characterized by inflammatory demyelination of the central nervous system (CNS) and involves activation of key inflammatory cells of both the adaptive and innate immune systems, which target and destroy both myelin and oligodendrocytes (the myelin-forming glial cells in the CNS). Key pathological features of the disease include autoimmune inflammation, axonal degeneration and demyelination (myelin loss), latter of which can occur in both white matter and gray matter. The key cell type damaged in MS is oligodendrocytes, which produce the insulating myelin sheath surrounding many axons in the CNS. Myelin and oligodendrocytes have critical roles. Myelin is responsible for promoting rapid, saltatory conduction of action potentials throughout much of the CNS. When myelin is lost in diseases such as MS, saltatory conduction is disrupted and conduction block can ensue. Myelin also provides a physical barrier for axons and thus serves to abrogate axonally directed, immune attack. Oligodendrocytes can also provide key nutritive support to axons in the healthy, quiescent state, which is compromised when oligodendrocytes are targeted (Nave and Werner, 2014). There is an emerging consensus that the progressive disability that ultimately ensues for many patients with MS correlates with the degree of accumulative axonal degeneration. It is also apparent that the extent of demyelination, and the degree of oligodendrocyte targeting, are likely to be relevant factors that dictate outcomes. Whilst it is well identified that spontaneous remyelination occurs after a demyelinative insult, the degree of remyelination within MS lesions is variable; generally MS lesions remyelinate relatively efficiently early in disease; however, at later stages many lesions remain chronically demyelinated (Trapp and Nave, 2008). These chronically demyelinated lesions typically contain oligodendrocyte progenitor cells (OPCs) and premyelinating oligodendrocytes that have “stalled” in their differentiation (Franklin et al., 2012). These findings suggest remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes, but a failure to differentiate into mature oligodendrocytes and to initiate new myelin formation.

An evidence-based case of acoustic/vestibular schwannoma

A vestibular schwannoma, often called an acoustic neuroma/schwannoma, is a benign primary intracranial tumor of the myelin-forming cells of the vestibulo-cochlear nerve (8 th cranial nerve). This tumor arises from the Schwann cells responsible for the myelin sheath that helps keep peripheral nerves insulated. [1] Approximately, 3000 cases are diagnosed each year in the United States with a prevalence of about 1 in 100,000 worldwide. It comprises 5-10% of all intracranial neoplasms in adults. Incidence peaks in the fifth and sixth decades and both sexes are affected equally. Studies in Denmark published in 2004 show the incidence of 17.4/million. Most acoustic neuromas are diagnosed in patients between the ages of 30 and 60, and men and women appear to be affected equally. [2] The case illustrated here is a rare one of acoustic/vestibular schwannoma a surgical conditions, treated with Lycopodium, which produced improvement on both subjective and objective parameters.

To myelinate or not to myelinate: fine tuning cAMP signaling in Schwann cells to balance cell proliferation and differentiation

cAMP signaling and the control of Schwann cell fate: The ubiquitous second messenger cyclic adenosine monophosphate (cAMP) controls a variety of cellular responses in a cell type-specific and stimulus-dependent manner through an elaborate network of signaling intermediaries that connect stimulation of cell membrane receptors (typically G protein-coupled receptors, GPCRs) to transcription factor activation. Schwann cells (SCs) are highly responsive to cAMP throughout their lifespan, as extensive research has shown that SC survival, lineage specification, proliferation and differentiation into myelin-forming cells require cAMP signaling.

Facial nerve schwannoma: A case report and review of the literature.

A vestibular schwannoma, often termed an acoustic neuroma, is a type of benign primary intracranial tumor of the myelin-forming cells of the vestibulocochlear nerve. The typical clinical presentation often includes ipsilateral sensorineural hearing loss/deafness, vertigo and tinnitus. In the present study, the case of a young male patient who presented with recurrent unilateral facial palsy without hearing impairment is presented. The patient was diagnosed with vestibular schwannoma and received steroidal treatment with prednisolone for two weeks. The patient’s facial weakness recovered three weeks following treatment, however, the tumor subsequently grew. The patient then underwent Gamma Knife radiosurgery with a margin dose of 13 Gy. Six months after the radiosurgery, the tumor was stable without progression, and the patient’s facial nerve function and hearing remained intact.

Oligodendrocyte Pathophysiology and Treatment Strategies in Cerebral Ischemia

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia-ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult-onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OLs, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OLs in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.