The translational biology of remyelination: Past, present, and future

Amongst neurological diseases, multiple sclerosis (MS) presents an attractive target for regenerative medicine. This is because the primary pathology, the loss of myelin-forming oligodendrocytes, can be followed by a spontaneous and efficient regenerative process called remyelination. While cell transplantation approaches have been explored as a means of replacing lost oligodendrocytes, more recently therapeutic approaches that target the endogenous regenerative process have been favored. This is in large part due to our increasing understanding of (1) the cell types within the adult brain that are able to generate new oligodendrocytes, (2) the mechanisms and pathways by which this achieved, and (3) an emerging awareness of the reasons why remyelination efficiency eventually fails. Here we review some of these advances and also highlight areas where questions remain to be answered in both the biology and translational potential of this important regenerative process. GLIA 2014;62:1905–191

Enhancing Central Nervous System Remyelination in Multiple Sclerosis

Recent studies on adult neural stem cells and the developmental biology of myelination have generated the expectation that neural precursors can repair the damaged central nervous system of multiple sclerosis patients where the endogenous remyelination process has failed. As a result, many laboratories are engaged in translational studies in which the goal is to design ways to promote remyelination and repair. Here we raise issues highlighted by prior experimental and human work that should be considered lest these studies become “lost in translation.

Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development

During peripheral nervous system (PNS) myelination, Schwann cells must interpret extracellular cues to sense their environment and regulate their intrinsic developmental program accordingly. The pathways and mechanisms involved in this process are only partially understood. We use tissue-specific conditional gene targeting to show that members of the Rho GTPases, cdc42 and rac1, have different and essential roles in axon sorting by Schwann cells. Our results indicate that although cdc42 is required for normal Schwann cell proliferation, rac1 regulates Schwann cell process extension and stabilization, allowing efficient radial sorting of axon bundles

Retinoid X Receptor activation reverses age-related deficiencies in myelin debris phagocytosis and CNS remyelination

Remyelination is a regenerative process that occurs through the formation of myelin sheaths by oligodendrocytes, which are recruited as oligodendrocyte progenitor cells (OPCs) after demyelination in diseases such as Multiple Sclerosis (MS).A key environmental factor regulating OPC differentiation is the fate of myelin debris generated during demyelination. Myelin debris contains inhibitors of OPC differentiation and thus its clearance by phagocytic macrophages is an important component of creating a lesion environment conducive to remyelination. The efficiency of debris clearance declines with age, contributing to the age-associated decline in remyelination. Therefore, understanding the mechanisms of the age-related decline in myelin debris phagocytosis is important for devising means to therapeutically reverse the decline in remyelination. The aim of this study was to determine the functional/molecular differences between young and old phagocytes involved in myelin debris clearance, thereby identifying therapeutically modifiable pathways associated with efficient myelin debris phagocytosis. In this study, we show that expression of genes involved in the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) pathways are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages. Disruption of RXR and PPAR using synthetic antagonists in young macrophages mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα knockout mice revealed that loss of RXR function in young mice caused delayed myelin debris uptake and slowed remyelination. Alternatively, receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The FDA-approved agonists bexarotene and pioglitazone, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profiles in MS patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. Activation of these pathways also enhances immunoregulatory markers on monocytes from MS patients, further suggesting the regeneration-promoting capacity of activating these pathways in phagocytes. These results reveal the RXR/PPAR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.This work was supported by the Gates-Cambridge Scholarship and NIH-Cambridge Partnership Progra

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis

The authors acknowledge the following support: The UK Multiple Sclerosis Society (MS50 to R.T.K., C.Z., and R.J.M.F.), The Adelson Medical Research Foundation (D.S.R., D.E.B., and R.J.M.F.), Intramural Research Program of NINDS/NIH (D.S.R.), European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (771411 to R.T.K.), The Lister Institute (R.T.K.), and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z to R.T.K. and R.J.M.F.). Publisher Copyright: © 2020 Elsevier Inc.Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.Peer reviewe

Enhanced axonal response of mitochondria to demyelination offers neuroprotection:implications for multiple sclerosis

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.</p

The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche

AbstractIschaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5weeks and 1year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase

Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation

Combination of searches for Higgs boson pairs in pp collisions at \sqrts = 13 TeV with the ATLAS detector

This letter presents a combination of searches for Higgs boson pair production using up to 36.1 fb(-1) of proton-proton collision data at a centre-of-mass energy root s = 13 TeV recorded with the ATLAS detector at the LHC. The combination is performed using six analyses searching for Higgs boson pairs decaying into the b (b) over barb (b) over bar, b (b) over barW(+)W(-), b (b) over bar tau(+)tau(-), W+W-W+W-, b (b) over bar gamma gamma and W+W-gamma gamma final states. Results are presented for non-resonant and resonant Higgs boson pair production modes. No statistically significant excess in data above the Standard Model predictions is found. The combined observed (expected) limit at 95% confidence level on the non-resonant Higgs boson pair production cross-section is 6.9 (10) times the predicted Standard Model cross-section. Limits are also set on the ratio (kappa(lambda)) of the Higgs boson self-coupling to its Standard Model value. This ratio is constrained at 95% confidence level in observation (expectation) to -5.0 &lt; kappa(lambda) &lt; 12.0 (-5.8 &lt; kappa(lambda) &lt; 12.0). In addition, limits are set on the production of narrow scalar resonances and spin-2 Kaluza-Klein Randall-Sundrum gravitons. Exclusion regions are also provided in the parameter space of the habemus Minimal Supersymmetric Standard Model and the Electroweak Singlet Model. For complete list of authors see http://dx.doi.org/10.1016/j.physletb.2019.135103</p

Searches for lepton-flavour-violating decays of the Higgs boson in s=13\sqrt{s}=13 TeV pp\mathit{pp} collisions with the ATLAS detector

This Letter presents direct searches for lepton flavour violation in Higgs boson decays, H → eτ and H → μτ , performed with the ATLAS detector at the LHC. The searches are based on a data sample of proton–proton collisions at a centre-of-mass energy √s = 13 TeV, corresponding to an integrated luminosity of 36.1 fb−1. No significant excess is observed above the expected background from Standard Model processes. The observed (median expected) 95% confidence-level upper limits on the leptonflavour-violating branching ratios are 0.47% (0.34+0.13−0.10%) and 0.28% (0.37+0.14−0.10%) for H → eτ and H → μτ , respectively.publishedVersio