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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. Chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes are known to inhibit OPC differentiation and remyelination. Here, the authors identify a novel CSPG synthesis inhibitor and find it can rescue OPC differentiation in vitro and accelerate remyelination in mice following focal demyelination.

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD. Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.

Background Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Methods We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 deficient  (EXTL2 -/- ) mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. Results The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genome-wide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2 −/− mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2 −/− mice had exacerbated axonal damage and myelin disruption relative to wild-type mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow-derived macrophages from EXTL2 −/− mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). Conclusions These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.

Background Intracerebral hemorrhage (ICH) is the predominant type of hemorrhagic stroke with high mortality and disability. In other neurological conditions, the deposition of extracellular matrix (ECM) molecules is a prominent obstacle for regenerative processes and an enhancer of neuroinflammation. Whether ECM molecules alter in composition after ICH, and which ECM members may inhibit repair, remain largely unknown in hemorrhagic stroke.The collagenase-induced ICH mouse model and an autopsied human ICH specimen were investigated for expression of ECM members by immunofluorescence microscopy. Confocal image z-stacks were analyzed with Imaris 3D to assess the association of immune cells and ECM molecules. Sections from a mouse model of multiple sclerosis were used as disease and staining controls. Tissue culture was employed to examine the roles of ECM members on oligodendrocyte precursor cells (OPCs).Results Amongst the lectican chondroitin sulphate proteoglycan (CSPG) members, neurocan but not aggrecan, versican-V1 and versican-V2 was prominently expressed in perihematomal tissue and lesion core compared to the contralateral area in murine ICH.Fibrinogen, fibronectin and heparan sulphate proteoglycan (HSPG) were also elevated after murine ICH while thrombospondin and tenascin-C was not. Confocal microscopy with Imaris 3D rendering co-localized neurocan, fibrinogen, fibronectin and HSPG molecules to Iba1 + microglia/macrophages or GFAP + astrocytes. Marked differentiation from the multiple sclerosis model was observed, the latter with high versican-V1 and negligible neurocan. In culture, purified neurocan inhibited adhesion and process outgrowth of OPCs, which are early steps in myelination in vivo. The prominent expression of neurocan in murine ICH was corroborated in human ICH sections.Conclusion ICH caused distinct alterations in ECM molecules. Amongst CSPG members, neurocan was selectively upregulated in both murine and human ICH. In tissue culture, neurocan impeded the properties of oligodendrocyte lineage cells.Alterations to the ECM in ICH may adversely affect reparative outcomes after stroke.

Insufficient physical activity is associated with increased relative risk of cardiometabolic disease and is an independent risk factor for mortality. Experimentally reducing physical activity rapidly induces insulin resistance, impairs glucose handling, and drives metabolic inflexibility. These adaptations manifest during the early stages of physical inactivity, even when energy balance is maintained, suggesting that inactivity‐mediated metabolic reprogramming is an early event that precedes changes in body composition. To identify mechanisms that promote metabolic adaptations associated with physical inactivity, we developed a mouse model of physical activity reduction that permits the study of inactivity in animals prior to the onset of overt changes in body composition. Adult mice were randomized into three groups: an inactive control group (standard rodent housing), an active control group (treadmill running 5 d/week for 6‐weeks), and an activity reduction group (treadmill running for 4‐weeks, followed by 2‐weeks of inactivity). Transcriptional profiling of gastrocnemius muscle identified seven transcripts uniquely altered by physical activity reduction compared to the inactive and active control groups. Most identified transcripts had reported functions linked to bioenergetic adaptation. Future studies will provide deeper characterization of the function(s) of each the identified transcripts while also determining how inactivity affects transcriptional regulation in other tissues.

Key Points Multiple sclerosis (MS) involves profound destruction of oligodendrocytes and myelin MRI and histological studies suggest that iron levels are dysregulated in MS: iron accumulates in grey matter and is depleted in normal-appearing white matter Iron accumulation promotes cytotoxicity through a variety of mechanisms, including chemical reactions leading to oxidative stress, increased proinflammatory cytokine levels, glutamate toxicity, and impaired DNA repair Iron is a cofactor for a variety of enzymes involved in maintaining the health of oligodendrocytes and myelin, and may be a crucial component of remyelination Treatments for iron excess in MS must address not only the increased iron levels within grey matter, but also the requirement for iron in remyelination and repair The extracellular matrix, a key regulator of remyelination, may also modulate iron availability Brain imaging and histopathological studies have suggested that iron plays a crucial part in the pathophysiology of multiple sclerosis (MS). In this Review, Yong and colleagues discuss the growing evidence of widespread dysregulation of iron metabolism associated with MS, from focal iron deposits around grey matter lesions to iron deficits in white matter that might interfere with remyelination and other cellular repair processes. The authors then outline several potential mechanisms for treating iron dysregulation that balance the trophic and toxic properties of this molecule. MRI and histological studies have shown global alterations in iron levels in the brains of patients with multiple sclerosis (MS), including increases in the iron stored by macrophages and microglia. Excessive free iron can be toxic, and accumulation of iron in MS has generally been thought to be detrimental. However, iron maintains the integrity of oligodendrocytes and myelin, and facilitates their regeneration following injury. The extracellular matrix, a key regulator of remyelination, might also modulate iron levels. This Review highlights key histological and MRI studies that have investigated changes in iron distribution associated with MS. Potential sources of iron, as well as iron regulatory proteins and the detrimental roles of excessive iron within the CNS, are also discussed, with emphasis on the importance of iron within cells for oxidative metabolism, proliferation and differentiation of oligodendrocytes, and myelination. In light of the beneficial and detrimental properties of iron within the CNS, we present considerations for treatments that target iron in MS. Such treatments must balance trophic and toxic properties of iron, by providing sufficient iron levels for remyelination and repair while avoiding excesses that might overwhelm homeostatic mechanisms and contribute to damage.

Iron's activity in the body can be two-faced. On the one hand it is integral to many enzymatic reactions; on the other hand it is toxic, with a great capacity for cellular damage. This review examines iron in the brain through the lens of multiple sclerosis (MS), reviewing the functions of intracellular and extracellular iron and their impact on the disease, as well as highlighting the focus of new research and controversial therapies. The primary cause of MS has remained enigmatic, ever since its first clinical documentation. Several studies have suggested a link between MS and iron. Abnormal iron accumulation has been found as deposits in MS lesions around cerebral veins, in the macrophages surrounding MS lesions, and also in deep brain structures. There are features of MS, such as the inflammatory environment and altered vasculature, which are important in highlighting mechanisms of how iron can accumulate, and also how iron dysregulation can create a positive feedback cycle that further promotes neurodegeneration and increased iron accumulation. This potential link between iron and MS has gained widespread attention, in part due to the controversial cerebrospinal venous insufficiency (CCSVI) hypothesis and \"Liberation Therapy\" first introduced by Dr. Zamboni in 2008. Determining the role of iron in MS will help provide a better insight to the different factions of scientists who disagree on whether MS is primarily an autoimmune disorder, or whether a neurodegenerative mechanism is the instigator.

Multiple sclerosis (MS), a progressive demyelinating disease of the brain and spinal cord, is the leading cause of nontraumatic neurological damage in young adults. Canada has one of the highest reported incidents of MS, with estimates between 55 and 240 per 100,000 individuals. Between 2009 and 2014, the MS Society of Canada provided over Can $90 million to researchers and, since 2013, has encouraged researchers to make both current and previous research products openly available. The goal of the study was to determine the open access (OA) cost implications and repository policies of journals frequently used by a sample of MS researchers. This study benchmarked current publishing preferences by MS Society of Canada researchers by examining the OA full-text availability of journal articles written by researchers funded between 2009 and 2014. Researchers were identified from the 2009 to 2014 annual MS Society of Canada Research Summaries. Articles were identified through searches in Web of Science, Scopus, Medline and Embase (both via OVID). Journal level analysis included comparison of OA policies, including article processing charges (APCs) and repository policies. Data were analyzed using descriptive statistics. There were 758 articles analyzed in this study, of which 288 (38.0%) were OA articles. The majority of authors were still relying on journal policies for deposit in PubMed Central or availability on publisher websites for OA. Gold OA journals accounted for 10.2% of the journals in this study and were associated with significantly lower APCs (US $1900) than in hybrid journals (US $3000). Review of the journal self-archiving options highlighted the complexity of stipulations that authors would have to navigate to legally deposit a version of their article. This study found that there are currently researcher- and publisher-imposed barriers to both the gold and green roads to OA. These results provide a current benchmark against which efforts to enhance openness can be measured and can serve as a reference point in future assessments of the impact of OA policies within this field. With funding agencies worldwide releasing OA mandates, future success in compliance will require changes to how researchers and publishers approach production and dissemination of research.

The extracellular matrix (ECM) of the central nervous system (CNS) is an interconnected network of proteins and sugars with critical roles in both homeostasis and disease. In neurological diseases, excessive ECM deposition and remodeling impact both injury and repair. CNS lesions of multiple sclerosis (MS), a chronic inflammatory and degenerative disease, cause prominent alterations of the ECM. However, there are a lack of data investigating how the multitude of ECM members change in relation to each other and how this affects the MS disease course. Here, we evaluated ECM changes in MS lesions compared to a control brain using databases generated in-house through spatial mRNA-sequencing and through a public resource of single-nucleus RNA sequencing previously published by Absinta and colleagues. These results underline the importance of publicly available datasets to find new targets of interest, such as the ECM. Both spatial and public datasets demonstrated widespread changes in ECM molecules and their interacting proteins, including alterations to proteoglycans and glycoproteins within MS lesions. Some of the altered ECM members have been described in MS, but other highly upregulated members, including the SPARC family of proteins, have not previously been highlighted. SPARC family members are upregulated in other conditions by reactive astrocytes and may influence immune cell activation and MS disease course. The profound changes to the ECM in MS lesions deserve more scrutiny as they impact neuroinflammation, injury, and repair.

Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease. Thus, the aim of this project was to determine the feasibility of systemic mitochondrial transfer for improving energy balance regulation in the setting of diet-induced obesity. We found that transplantation of mitochondria from lean mice into mice with diet-induced obesity attenuated adiposity gains by increasing energy expenditure and promoting the mobilization and oxidation of lipids. Additionally, mice that received exogenous mitochondria demonstrated improved glucose uptake, greater insulin responsiveness, and complete reversal of hepatic steatosis. These changes were, in part, driven by adaptations occurring in white adipose tissue. Together, these findings are proof-of-principle that mitochondrial transplantation is an effective therapeutic strategy for limiting the deleterious metabolic effects of diet-induced obesity in mice.Competing Interest StatementThe authors have declared no competing interest.