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Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m + microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a devastating autoimmune disease that leads to profound disability. This disability arises from the stochastic, regional loss of myelin-the insulating sheath surrounding neurons-in the central nervous system (CNS). The demyelinated regions are dominated by the brain's resident macrophages: microglia. Microglia perform a variety of functions in MS and are thought to initiate and perpetuate demyelination through their interactions with peripheral immune cells that traffic into the brain. However, microglia are also likely essential for recruiting and promoting the differentiation of cells that can restore lost myelin in a process known as remyelination. Given these seemingly opposing functions, an overarching beneficial or detrimental role is yet to be ascribed to these immune cells. In this chapter, we will discuss microglia dynamics throughout the MS disease course and probe the apparent dichotomy of microglia as the drivers of both demyelination and remyelination., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1β, and -18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD +/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD -/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd +/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd -/- animals. CPZ-exposed Gsdmd +/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd -/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd -/- animals. [ 18 F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd -/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Decades of research into chronic pain has deepened our understanding of the cellular mechanisms behind this process. However, a failure to consider the biological variable of sex has limited the application of these breakthroughs into clinical application. In the present study, we investigate fundamental differences in chronic pain between male and female mice resulting from inflammatory activation of the innate immune system. We provide evidence that female mice are more sensitive to the effects of macrophages. Injecting small volumes of media conditioned by either unstimulated macrophages or macrophages stimulated by the inflammatory molecule TNFα lead to increased pain sensitivity only in females. Interestingly, we find that TNFα conditioned media leads to a more rapid resolution of mechanical hypersensitivity and altered immune cell recruitment to sites of injury. Furthermore, male and female macrophages exhibit differential polarization characteristics and motility after TNFα stimulation, as well as a different profile of cytokine secretions. Finally, we find that the X-linked gene Tlr7 is critical in the facilitating the adaptive resolution of pain in models of acute and chronic inflammation in both sexes. Altogether, these findings suggest that although the cellular mechanisms of pain resolution may differ between the sexes, the study of these differences may yield more targeted approaches with clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Social isolation is a profound form of psychological stress that impacts the mental health of a large proportion of society. Other experimental models of stress have demonstrated a microglia response that serves either a protective or pathological function. However, the effect of adult social isolation on microglia has not been thoroughly investigated. We measured microglia territory, branching, end points and phagocytic-lysosomal activity in group housed C57Bl/6 mice and mice that were socially isolated for 2 weeks. Our results show that the dorsomedial hypothalamus and hippocampal CA2 region of adult male mice undergo increased microglia volume, territory and endpoints following social isolation, whereas females exhibit this increase in the hypothalamus only. Males exhibited decreases in the phagocytic-lysosomal marker CD68 in microglia in these regions, whereas females showed an increase in CD68 in the hypothalamus suggesting sexually dimorphic and brain region-specific change in microglia state in response to social isolation. The prefrontal cortex, central amygdala, nucleus accumbens shell and visual cortex did not exhibit changes in microglia structure in either male or female mice. These data show that microglia in different brain regions undergo a distinct response to social isolation which may account for changes in cognition and behaviour associated with this prevalent form of psychological stress., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Dorsal root ganglia (DRGs) are peripheral structures adjacent to the dorsal horn of the spinal cord, which house the cell bodies of sensory neurons as well as various other cell types. Published culture protocols often refer to whole dissociated DRG cultures as being neuronal, despite the presence of fibroblasts, Schwann cells, macrophages, and lymphocytes. While these whole DRG cultures are sufficient for imaging applications where neurons can be discerned based on morphology or staining, protein or RNA homogenates collected from these cultures are not primarily neuronal in origin. Here, we describe an immunopanning sequence for cultured mouse DRGs. The goal of this method is to enrich DRG cultures for neurons by removing other cell types. Immunopanning refers to a method of removing cell types by adhering antibodies to cell culture dishes. Using these dishes, we can negatively select against and reduce the number of fibroblasts, immune cells, and Schwann cells in culture. This method allows us to increase the percentage of neurons in cultures.

Background: Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood., Methods: To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response., Results: The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination., Conclusions: Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state., (© 2022. The Author(s).)

Multiple Sclerosis (MS) is an autoimmune disease with notable sex differences. Women are not only more likely to develop MS but are also more likely than men to experience neuropathic pain in the disease. It has been postulated that neuropathic pain in MS can originate in the peripheral nervous system at the level of the dorsal root ganglia (DRG), which houses primary pain sensing neurons (nociceptors). These nociceptors become hyperexcitable in response to inflammation, leading to peripheral sensitization and eventually central sensitization, which maintains pain long-term. The mouse model experimental autoimmune encephalomyelitis (EAE) is a good model for human MS as it replicates classic MS symptoms including pain. Using EAE mice as well as naïve primary mouse DRG neurons cultured in vitro, we sought to characterize sex differences, specifically in peripheral sensory neurons. We found sex differences in the inflammatory profile of the EAE DRG, and in the TNFα downstream signaling pathways activated intracellularly in cultured nociceptors. We also found increased cell death with TNFα treatment. Given that TNFα signaling has been shown to initiate intrinsic apoptosis through mitochondrial disruption, this led us to investigate sex differences in the mitochondria's response to TNFα. Our results demonstrate that male sensory neurons are more sensitive to mitochondrial stress, making them prone to neuronal injury. In contrast, female sensory neurons appear to be more resistant to mitochondrial stress and exhibit an inflammatory and regenerative phenotype that may underlie greater nociceptor hyperexcitability and pain. Understanding these sex differences at the level of the primary sensory neuron is an important first step in our eventual goal of developing sex-specific treatments to halt pain development in the periphery before central sensitization is established., (© 2022. The Author(s).)

High dimensional single-cell analysis such as single cell and single nucleus RNA sequencing (sc/snRNAseq) are currently being widely applied to explore microglia diversity. The use of sc/snRNAseq provides a powerful and unbiased approach to deconvolve heterogeneous cellular populations. However, sc/snRNAseq and analyses pipelines are designed to find heterogeneity. Indeed, cellular heterogeneity is often the most frequently reported finding. In this Perspective, we consider the ubiquitous concept of heterogeneity focusing on its application to microglia research and its influence on the field of neuroimmunology. We suggest that a clear understanding of the semantic and biological implications of microglia heterogeneity is essential for mitigating confusion among researchers., (© 2022. The Author(s).)

Background: The dietary consumption of cuprizone - a copper chelator - has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action 'intrinsic cell damage'. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells - neutrophils or T-cells. We term this mode of action 'extrinsic cellular damage'. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS., (© 2022. The Author(s).)

There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing-remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood-brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent., (© 2022. The Author(s).)

The dynamic expansions and contractions of the microglia population in the central nervous system (CNS) to achieve homeostasis are likely vital for their function. Microglia respond to injury or disease but also help guide neurodevelopment, modulate neural circuitry throughout life, and direct regeneration. Throughout these processes, microglia density changes, as does the volume of area that each microglia surveys. Given that microglia are responsible for sensing subtle alterations to their environment, a change in their density could affect their capacity to mobilize rapidly. In this review, we attempt to synthesize the current literature on the ligands and conditions that promote microglial proliferation across development, adulthood, and neurodegenerative conditions. Microglia display an impressive proliferative capacity during development and in neurodegenerative diseases that is almost completely absent at homeostasis. However, the appropriate function of microglia in each state is critically dependent on density fluctuations that are primarily induced by proliferation. Proliferation is a natural microglial response to insult and often serves neuroprotective functions. In contrast, inappropriate microglial proliferation, whether too much or too little, often precipitates undesirable consequences for nervous system health. Thus, fluctuations in the microglia population are tightly regulated to ensure these immune cells can execute their diverse functions., (© 2021 Wiley Periodicals LLC.)

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS). Repair through remyelination can be extensive, but quantification of remyelination remains challenging. To date, no method for standardized digital quantification of remyelination of MS lesions exists. This methodological study aims to present and validate a novel standardized method for myelin quantification in progressive MS brains to study myelin content more precisely. Fifty-five MS lesions in 32 tissue blocks from 14 progressive MS cases and five tissue blocks from 5 non-neurological controls were sampled. MS lesions were selected by macroscopic investigation of WM by standard histopathological methods. Tissue sections were stained for myelin with luxol fast blue (LFB) and histological assessment of de- or remyelination was performed by light microscopy. The myelin quantity was estimated with a novel myelin quantification method (MQM) in ImageJ. Three independent raters applied the MQM and the inter-rater reliability was calculated. We extended the method to diffusely appearing white matter (DAWM) and encephalitis to test potential wider applicability of the method. Inter-rater agreement was excellent (ICC = 0.96) and there was a high reliability with a lower- and upper limit of agreement up to -5.93% to 18.43% variation in myelin quantity. This study builds on the established concepts of histopathological semi-quantitative assessment of myelin and adds a novel, reliable and accurate quantitative measurement tool for the assessment of myelination in human post-mortem samples.

With substantial progress in experimental therapeutics to enhance the nervous system's capacity for remyelination, new methods to detect myelin are important advances. We discuss a small-angle X-ray scattering tensor tomography approach presented recently by Georgiadis et al. and the method's promise in providing a new window into the brain to evaluate myelin integrity in health and disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: CD33 is genetically linked to Alzheimer's disease (AD) susceptibility through differential expression of isoforms in microglia. The role of the human CD33 short isoform (hCD33m), preferentially encoded by an AD-protective CD33 allele (rs12459419T), is unknown. Here, we test whether hCD33m represents a loss-of-function or gain-of-function variant., Methods: We have developed two models to test the role of hCD33m. The first is a new strain of transgenic mice expressing hCD33m in the microglial cell lineage. The second is U937 cells where the CD33 gene was disrupted by CRISPR/Cas9 and complemented with different variants of hCD33. Primary microglia and U937 cells were tested in phagocytosis assays and single cell RNA sequencing (scRNAseq) was carried out on the primary microglia. Furthermore, a new monoclonal antibody was developed to detect hCD33m more efficiently., Results: In both primary microglia and U937 cells, we find that hCD33m enhances phagocytosis. This contrasts with the human CD33 long isoform (hCD33M) that represses phagocytosis, as previously demonstrated. As revealed by scRNAseq, hCD33m + microglia are enriched in a cluster of cells defined by an upregulated expression and gene regulatory network of immediate early genes, which was further validated within microglia in situ. Using a new hCD33m-specific antibody enabled hCD33m expression to be examined, demonstrating a preference for an intracellular location. Moreover, this newly discovered gain-of-function role for hCD33m is dependent on its cytoplasmic signaling motifs, dominant over hCD33M, and not due to loss of glycan ligand binding., Conclusions: These results provide strong support that hCD33m represents a gain-of-function isoform and offers insight into what it may take to therapeutically capture the AD-protective CD33 allele.

Multiple Sclerosis (MS) is a neurodegenerative disease characterized by multiple focal lesions, ongoing demyelination and, for most people, a lack of remyelination. MS lesions are enriched with monocyte-derived macrophages and brain-resident microglia that, together, are likely responsible for much of the immune-mediated neurotoxicity. However, microglia and macrophage also have documented neuroprotective and regenerative roles, suggesting a potential diversity in their functions. Linked with microglial functional diversity, they take on diverse phenotypes developmentally, regionally and across disease conditions. Advances in technologies such as single-cell RNA sequencing and mass cytometry of immune cells has led to dramatic developments in understanding the phenotypic changes of microglia and macrophages. This review highlights the origins of microglia, their heterogeneity throughout normal ageing and their contribution to pathology and repair, with a specific focus on autoimmunity and MS. As phenotype dictates function, the emerging heterogeneity of microglia and macrophage populations in MS offers new insights into the potential immune mechanisms that result in inflammation and regeneration., (Copyright © 2020 Zia, Rawji, Michaels, Burr, Kerr, Healy and Plemel.)

Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of Cybb , the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx 3 cr1 CreER /+ :Rosa26 tdTom /+ mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide. SIGNIFICANCE STATEMENT Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis., (Copyright © 2020 the authors.)

The article Niacin‑mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI., (© 2019 Wiley Periodicals, Inc.)

Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling. Although blood-derived macrophages acutely infiltrated the demyelinated lesion, microglia progressively monopolized the lesion environment where they surrounded infiltrating macrophages. In the microglia-devoid sciatic nerve, the infiltrating macrophage response was sustained. In the CNS, the preferential proliferation of microglia and sparse microglia death contributed to microglia dominating the lesion. Microglia ablation reversed the spatial restriction of macrophages with the demyelinated spinal cord, highlighting an unrealized macrophages-microglia interaction. The restriction of peripheral inflammation by microglia may be a previously unidentified mechanism by which the CNS maintains its "immune privileged" status., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that involves demyelination and axonal degeneration. Although substantial progress has been made in drug development for relapsing-remitting MS, treatment of the progressive forms of the disease, which are characterized clinically by the accumulation of disability in the absence of relapses, remains unsatisfactory. This unmet clinical need is related to the complexity of the pathophysiological mechanisms involved in MS progression. Chronic inflammation, which occurs behind a closed blood-brain barrier with activation of microglia and continued involvement of T cells and B cells, is a hallmark pathophysiological feature. Inflammation can enhance mitochondrial damage in neurons, which, consequently, develop an energy deficit, further reducing axonal health. The growth-inhibitory and inflammatory environment of lesions also impairs remyelination, a repair process that might protect axons from degeneration. Moreover, neurodegeneration is accelerated by the altered expression of ion channels on denuded axons. In this Review, we discuss the current understanding of these disease mechanisms and highlight emerging therapeutic strategies based on these insights, including those targeting the neuroinflammatory and degenerative aspects as well as remyelination-promoting approaches.

In diseases such as multiple sclerosis (MS), inflammation can injure the myelin sheath that surrounds axons, a process known as demyelination. The spontaneous regeneration of myelin, called remyelination, is associated with restoration of function and prevention of axonal degeneration. Boosting remyelination with therapeutic intervention is a promising new approach that is currently being tested in several clinical trials. The endogenous regulation of remyelination is highly dependent on the immune response. In this review article, we highlight the cell biology of remyelination and its regulation by innate immune cells. For the purpose of this review, we discuss the roles of microglia, and also astrocytes and oligodendrocyte progenitor cells (OPCs) as they are being increasingly recognized to have immune cell functions., (Copyright © 2019 Baaklini, Rawji, Duncan, Ho and Plemel.)

Remyelination occurs after spinal cord injury (SCI) but its functional relevance is unclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination after contusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive (PDGFRα-positive) oligodendrocyte progenitor cells (OPCs) in mice prior to SCI. While OPC proliferation and density are not altered by Myrf inducible knockout after SCI, the accumulation of new oligodendrocytes is largely prevented. This greatly inhibits myelin regeneration, resulting in a 44% reduction in myelinated axons at the lesion epicenter. However, spontaneous locomotor recovery after SCI is not altered by remyelination failure. In controls with functional MYRF, locomotor recovery precedes the onset of most oligodendrocyte myelin regeneration. Collectively, these data demonstrate that MYRF expression in PDGFRα-positive cell derived oligodendrocytes is indispensable for myelin regeneration following contusive SCI but that oligodendrocyte remyelination is not required for spontaneous recovery of stepping.

Although immune attack against central nervous system (CNS) myelin is a central feature of multiple sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit pathological immune responses with radiological and histological properties similar to MS lesions. A subtle myelinopathy induced by abbreviated cuprizone treatment, coupled with subsequent immune stimulation, resulted in lesions of inflammatory demyelination. The degree of myelin injury dictated the resulting immune response; biochemical damage that was too limited or too extensive failed to trigger overt pathology. An inhibitor of peptidyl arginine deiminases (PADs), enzymes that alter myelin structure and correlate with MS lesion severity, mitigated pathology even when administered only during the myelin-altering phase. Moreover, cultured splenocytes were reactive against donor myelin isolates, a response that was substantially muted when splenocytes were exposed to myelin from donors treated with PAD inhibitors. By showing that a primary biochemical myelinopathy can trigger secondary pathological inflammation, "cuprizone autoimmune encephalitis" potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy., Competing Interests: The authors declare no conflict of interest.

Aging impairs regenerative processes including remyelination, the synthesis of a new myelin sheath. Microglia and other infiltrating myeloid cells such as macrophages are essential for remyelination through mechanisms that include the clearance of inhibitory molecules within the lesion. Prior studies have shown that the quantity of myeloid cells and the clearance of inhibitory myelin debris are deficient in aging, contributing to the decline in remyelination efficiency with senescence. It is unknown, however, whether the impaired clearance of debris is simply the result of the reduced number of phagocytes or if the dynamic activity of myeloid cells within the demyelinating plaque also declines with aging and this question is relevant to the proper design of therapeutics to mobilize myeloid cells for repair. Herein, we describe a high-resolution multiphoton ex vivo live imaging protocol that visualizes individual myelinated/demyelinated axons and lipid-containing myeloid cells to investigate the demyelinated lesion of aging female mice. We found that aging lesions have fewer myeloid cells and that these have reduced phagocytosis of myelin. Although the myeloid cells are actively migratory within the lesion of young mice and have protrusions that seem to survey the environment, this motility and surveillance is significantly reduced in aging mice. Our results emphasize the necessity of not only increasing the number of phagocytes, but also enhancing their activity once they are within demyelinated lesions. The high-resolution live imaging of demyelinated lesions can serve as a platform with which to discover pharmacological agents that rejuvenate intralesional remodeling that promotes the repair of plaques. SIGNIFICANCE STATEMENT The repair of myelin after injury depends on myeloid cells that clear debris and release growth factors. As organisms age, remyelination becomes less efficient correspondent with fewer myeloid cells that populate the lesions. It is unknown whether the dynamic activity of cells within lesions is also altered with age. Herein, using high-resolution multiphoton ex vivo live imaging with several novel features, we report that myeloid cells within demyelinated lesions of aging mice have reduced motility, surveillance, and phagocytic activity, suggesting an intralesional impairment that may contribute to the age-related decline in remyelination efficiency. Medications to stimulate deficient aging myeloid cells should not only increase their representation, but also enter into lesions to stimulate their activity., (Copyright © 2018 the authors 0270-6474/18/381973-16$15.00/0.)

For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice. We found that LPC nonspecifically disrupted myelin lipids. LPC integrated into cellular membranes and rapidly induced cell membrane permeability; in mice, LPC injury was phenocopied by other lipid disrupting agents. Interestingly, following its injection into white matter, LPC was cleared within 24 hr but by five days there was an elevation of endogenous LPC that was not associated with damage. This elevation of LPC in the absence of injury raises the possibility that the brain has mechanisms to buffer LPC. In support, LPC injury in culture was significantly ameliorated by albumin buffering. These results shed light on the mechanisms of LPC injury and homeostasis., (© 2017 Wiley Periodicals, Inc.)

It is widely recognized that myelination of axons greatly enhances the speed of signal transmission. An exciting new finding is the dynamic communication between axons and their myelin-forming oligodendrocytes, including activity-dependent signalling from axon to myelin. The oligodendrocyte-myelin complex may in turn respond by providing metabolic support or alter subtle myelin properties to modulate action potential propagation. In this Opinion, we discuss what is known regarding the molecular physiology of this novel, synapse-like communication and speculate on potential roles in disease states including multiple sclerosis, schizophrenia and Alzheimer disease. An emerging appreciation of the contribution of white-matter perturbations to neurological dysfunction identifies the axo-myelinic synapse as a potential novel therapeutic target.

This corrects the article DOI: 10.1038/nrn.2017.128.

Spontaneous remyelination occurs after spinal cord injury (SCI), but the extent of myelin repair and identity of the cells responsible remain incompletely understood and contentious. We assessed the cellular origin of new myelin by fate mapping platelet-derived growth factor receptor α (PDGFRα), Olig2+, and P0+ cells following contusion SCI in mice. Oligodendrocyte precursor cells (OPCs; PDGFRα+) produced oligodendrocytes responsible for de novo ensheathment of ∼30% of myelinated spinal axons at injury epicenter 3 months after SCI, demonstrating that these resident cells are a major contributor to oligodendrocyte regeneration. OPCs also produced the majority of myelinating Schwann cells in the injured spinal cord; invasion of peripheral myelinating (P0+) Schwann cells made only a limited contribution. These findings reveal that PDGFRα+ cells perform diverse roles in CNS repair, as multipotential progenitors that generate both classes of myelinating cells. This endogenous repair might be exploited as a therapeutic target for CNS trauma and disease. SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to profound functional deficits, though substantial numbers of axons often survive. One possible explanation for these deficits is loss of myelin, creating conduction block at the site of injury. SCI leads to oligodendrocyte death and demyelination, and clinical trials have tested glial transplants to promote myelin repair. However, the degree and duration of myelin loss, and the extent and mechanisms of endogenous repair, have been contentious issues. Here, we use genetic fate mapping to demonstrate that spontaneous myelin repair by endogenous oligodendrocyte precursors is much more robust than previously recognized. These findings are relevant to many types of CNS pathology, raising the possibility that CNS precursors could be manipulated to repair myelin in lieu of glial transplantation., (Copyright © 2017 the authors 0270-6474/17/378635-20$15.00/0.)

Multiple sclerosis is characterized by inflammatory activity that results in destruction of the myelin sheaths that enwrap axons. The currently available medications for multiple sclerosis are predominantly immune-modulating and do not directly promote repair. White matter regeneration, or remyelination, is a new and exciting potential approach to treating multiple sclerosis, as remyelination repairs the damaged regions of the central nervous system. A wealth of new strategies in animal models that promote remyelination, including the repopulation of oligodendrocytes that produce myelin, has led to several clinical trials to test new reparative therapies. In this Review, we highlight the biology of, and obstacles to, remyelination. We address new strategies to improve remyelination in preclinical models, highlight the therapies that are currently undergoing clinical trials and discuss the challenges of objectively measuring remyelination in trials of repair in multiple sclerosis.

Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase π positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure.

Spinal cord injury can lead to severe motor, sensory and autonomic dysfunction. Currently, there is no effective treatment for the injured spinal cord. The transplantation of Schwann cells, neural stem cells or progenitor cells, olfactory ensheathing cells, oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury. However, little is known about the mechanisms through which these individual cell types promote repair and functional improvements. The five most commonly proposed mechanisms include neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration. A better understanding of the mechanisms whereby these cells promote functional improvements, as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury, will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.

Cellular injury and death are ubiquitous features of disease, yet tools to detect them are limited and insensitive to subtle pathological changes. Acridine orange (AO), a nucleic acid dye with unique spectral properties, enables real-time measurement of RNA and DNA as proxies for cell viability during exposure to various noxious stimuli. This tool illuminates spectral signatures unique to various modes of cell death, such as cells undergoing apoptosis versus necrosis/necroptosis. This new approach also shows that cellular RNA decreases during necrotic, necroptotic, and apoptotic cell death caused by demyelinating, ischemic, and traumatic injuries, implying its involvement in a wide spectrum of tissue pathologies. Furthermore, cells with pathologically low levels of cytoplasmic RNA are detected earlier and in higher numbers than with standard markers including TdT-mediated dUTP biotin nick-end labeling and cleaved caspase 3 immunofluorescence. Our technique highlights AO-labeled cytoplasmic RNA as an important early marker of cellular injury and a sensitive indicator of various modes of cell death in a range of experimental models., (© 2017 Plemel et al.)

Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments for multiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base., Objective: We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS., Methods: Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results., Results: Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit., Conclusion: OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients., (© The Author(s), 2015.)

Historically, the immune response after spinal cord injury was considered largely detrimental owing to the release of neurotoxic factors. While there is validity to this view, there is much greater heterogeneity of immune cells than was previously realized. Associated with this heterogeneity of immune cell subtypes, there is diversity of functions of immune cells that is still poorly understood after spinal cord injury. Modulating the immune system requires improved understanding of the major players: those immune cell subtypes that are more detrimental than beneficial and those that are important in repair. In this review we will discuss the early findings that supported the use of various anti-inflammatory medications as well as the evolving concept that not all immune subtypes are detrimental and some might even be beneficial. In the last section we will highlight the need to characterize better the role of immune cell subsets in the hopes of developing potential therapeutic targets for the future., (Copyright © 2014 Elsevier Inc. All rights reserved.)

After spinal cord injury (SCI) there is prolonged and dispersed oligodendrocyte cell death that is responsible for widespread demyelination. To regenerate this lost myelin, many investigators have transplanted myelin-producing cells as a treatment for contusive SCI. There are several documented examples of cellular transplantation improving function after injury, with the degree of myelin regeneration correlating with functional recovery. On the basis of these findings, remyelination is hypothesized to be a beneficial strategy to promote recovery after injury. As cellular transplantation is now entering clinical trials for treatment of SCI, it is important to dissect carefully whether accelerating remyelination after SCI is a valid clinical target. In this review we will discuss the consequences of demyelination and the potential benefits of remyelination as it relates to injury. Prolonged demyelination is hypothesized to enhance axonal vulnerability to degeneration, and is thereby thought to contribute to the axonal degeneration that underlies the permanent functional losses associated with SCI. Currently, strategies to promote remyelination after SCI are largely limited to cellular transplantation. This review discusses those strategies as well as new, and largely untested, modes of therapy that aim to coax endogenous cells residing adjacent to the injury site to differentiate in order to replace lost myelin., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Myelin loss is a hallmark of multiple sclerosis (MS) and promoting central nervous system myelin repair has become a major therapeutic target. Despite the presence of oligodendrocytes precursors cells (OPCs) in chronic lesions of MS, remyelination often fails. The mechanism underlying this failure of remyelination remains unknown, but it is hypothesized that environmental cues act to inhibit the maturation/differentiation of oligodendroglia, preventing remyelination. The rate of CNS remyelination is correlated to the speed of phagocytosis of myelin debris, which is present following demyelination and trauma. Thus, myelin debris could inhibit CNS remyelination. Here, we demonstrate that OPCs cultured on myelin were robustly inhibited in their maturation, as characterized by the decreased expression of immature and mature oligodendrocytes markers, the impaired production of myelin gene products, as well as their stalled morphological complexity relative to OPCs cultured on a control substrate. OPCs in contact with myelin stopped proliferating and decreased the expression of OPC markers to a comparable degree as cells grown on a control substrate. The expression of two transcription factors known to prevent OPC differentiation and maturation were increased in cells that were in contact with myelin: inhibitor of differentiation family (ID) members 2 and 4. Overexpression of ID2 and ID4 in OPCs was previously reported to decrease the percentage of cells expressing mature oligodendrocyte markers. However, knockdown of ID2 and/or ID4 in OPCs did not increase oligodendroglial maturation on or off of myelin, suggesting that contact with myelin regulates additional regulatory elements., (Copyright © 2013 Wiley Periodicals, Inc.)

Remyelination following spinal cord injury (SCI) is thought to be incomplete; demyelination is reported to persist chronically and is proposed as a compelling therapeutic target. Yet most reports do not distinguish between the myelin status of intact axons and injury-severed axons whose proximal stumps persist but provide no meaningful function. We previously found full remyelination of spared, intact rubrospinal axons caudal to the lesion in chronic mouse SCI. However, the clinical concept of chronically demyelinated spared axons remains controversial. Since mouse models may have limitations in clinical translation, we asked whether the capacity for full remyelination is conserved in clinically relevant chronic rat SCI. We determined myelin status by examining paranodal protein distribution on anterogradely labeled, intact corticospinal and rubrospinal axons throughout the extent of the lesion. Demyelination was evident on proximal stumps of severed axons, but not on intact axons. For the first time, we demonstrate that a majority of intact axons exhibit remyelination (at least one abnormally short internode, <100 μm). Remarkably, shortened internodes were significantly concentrated at the lesion epicenter and individual axons were thinned by 23% compared with their rostral and caudal zones. Mathematical modeling predicted a 25% decrease in conduction velocity at the lesion epicenter due to short internodes and axonal thinning. In conclusion, we do not find a large chronically demyelinated population to target with remyelination therapies. Interventions may be better focused on correcting structural or molecular abnormalities of regenerated myelin.

Spinal cord injury (SCI) results in substantial oligodendrocyte death and subsequent demyelination leading to white-matter defects. Cell replacement strategies to promote remyelination are under intense investigation; however, the optimal cell for transplantation remains to be determined. We previously isolated a platelet-derived growth factor (PDGF)-responsive neural precursor (PRP) from the ventral forebrain of fetal mice that primarily generates oligodendrocytes, but also astrocytes and neurons. Importantly, human PRPs were found to possess a greater capacity for oligodendrogenesis than human epidermal growth factor- and/or fibroblast growth factor-responsive neural stem cells. Therefore, we tested the potential of PRPs isolated from green fluorescent protein (GFP)-expressing transgenic mice to remyelinate axons in the injured rat spinal cord. PRPs were transplanted 1 week after a moderate thoracic (T9) spinal cord contusion in adult male rats. After initial losses, PRP numbers remained stable from 2 weeks posttransplantation onward and those surviving cells integrated into host tissue. Approximately one-third of the surviving cells developed the typical branched phenotype of mature oligodendrocytes, expressing the marker APC-CC1. The close association of GFP cells with myelin basic protein as well as with Kv1.2 and Caspr in the paranodal and juxtaparanodal regions of nodes of Ranvier indicated that the transplanted cells successfully formed mature myelin sheaths. Transplantation of PRPs into dysmyelinated Shiverer mice confirmed the ability of PRP-derived cells to produce compact myelin sheaths with normal periodicity. These findings indicate that PRPs are a novel candidate for CNS myelin repair, although PRP-derived myelinating oligodendrocytes were insufficient to produce behavioral improvements in our model of SCI., (Copyright © 2011 Wiley‐Liss, Inc.)

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.