Special Issue "Myelin Repair"

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A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (30 April 2013)

Special Issue Editor

Guest Editor
Dr. Randall D. McKinnon

Department of Surgery, UMDNJ-RWJ Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
Website | E-Mail
Phone: +1 732 235 4419
Fax: +1 732 235 4477
Interests: CNS myelin development; growth factors; endogenous repair; transplants; stem cell programming; somatic cell reprogramming

Special Issue Information

Dear Colleagues,

Myelin sheaths that insulate and nourish CNS axons are produced by oligodendrocytes, highly metabolic cells that are vulnerable to trauma induced neurotoxicity and to autoimmune attack in diseases such as multiple sclerosis. This special issue will collect articles that address ongoing research into promoting myelin repair, including strategies to suppress innate immune attack, to promote endogenous repair processes, and to supplement this repair with exogenous cell grafts.

Dr. Randall D. McKinnon
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 600 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • Autoimmune disease
  • Brain repair
  • Cell transplants
  • CNS myelin
  • Multiple sclerosis
  • Stem cells
  • Oligodendrocyte

Published Papers (7 papers)

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Research

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Open AccessArticle White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors
Brain Sci. 2013, 3(4), 1461-1482; doi:10.3390/brainsci3041461
Received: 8 August 2013 / Revised: 15 October 2013 / Accepted: 28 October 2013 / Published: 12 November 2013
Cited by 3 | PDF Full-text (932 KB) | HTML Full-text | XML Full-text
Abstract
Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of
[...] Read more.
Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessArticle Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease
Brain Sci. 2013, 3(4), 1417-1444; doi:10.3390/brainsci3041417
Received: 24 July 2013 / Revised: 13 August 2013 / Accepted: 18 September 2013 / Published: 30 September 2013
Cited by 4 | PDF Full-text (3013 KB) | HTML Full-text | XML Full-text
Abstract
Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary
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Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary inflammatory responses inside and outside of the nervous system. In this study, we show that the metabolic stress pathway known as the unfolded protein response (UPR) leads to secondary activation of the immune system. First, we observe innate immune system activation in autopsy specimens from Pelizaeus-Merzbacher disease (PMD) patients and mouse models stemming from PLP1 gene mutations. Second, missense mutations in mildly- and severely-affected Plp1-mutant mice exhibit immune-associated expression profiles with greater disease severity causing an increasingly proinflammatory environment. Third, and unexpectedly, we find little evidence for dysregulated expression of major antioxidant pathways, suggesting that the unfolded protein and oxidative stress responses are separable. Together, these data show that UPR activation can precede innate and/or adaptive immune system activation and that neuroinflammation can be titrated by metabolic stress in oligodendrocytes. Whether or not such activation leads to autoimmune disease in humans is unclear, but the case report of steroid-mitigated symptoms in a PMD patient initially diagnosed with multiple sclerosis lends support. Full article
(This article belongs to the Special Issue Myelin Repair)
Figures

Open AccessArticle Damage to Myelin and Oligodendrocytes: A Role in Chronic Outcomes Following Traumatic Brain Injury?
Brain Sci. 2013, 3(3), 1374-1394; doi:10.3390/brainsci3031374
Received: 6 May 2013 / Revised: 23 August 2013 / Accepted: 2 September 2013 / Published: 16 September 2013
Cited by 5 | PDF Full-text (1897 KB) | HTML Full-text | XML Full-text
Abstract
There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve
[...] Read more.
There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve fibers in adult guinea-pigs was used to test the hypothesis that damage to the myelin sheath and oligodendrocytes of the optic nerve fibers may contribute to, or facilitate, the continuance of axonal loss. Myelin dislocations occur within internodal myelin of larger axons within 1–2 h of TBI. The myelin dislocations contain elevated levels of free calcium. The volume of myelin dislocations increase with greater survival and are associated with disruption of the axonal cytoskeleton leading to secondary axotomy. Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI. As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter. Full article
(This article belongs to the Special Issue Myelin Repair)

Review

Jump to: Research

Open AccessReview Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination
Brain Sci. 2013, 3(3), 1282-1324; doi:10.3390/brainsci3031282
Received: 8 July 2013 / Revised: 12 August 2013 / Accepted: 12 August 2013 / Published: 28 August 2013
Cited by 11 | PDF Full-text (1599 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+
[...] Read more.
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessReview Reprogramming Cells for Brain Repair
Brain Sci. 2013, 3(3), 1215-1228; doi:10.3390/brainsci3031215
Received: 13 June 2013 / Revised: 27 July 2013 / Accepted: 30 July 2013 / Published: 6 August 2013
PDF Full-text (325 KB) | HTML Full-text | XML Full-text
Abstract
At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to
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At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia. In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models. Mesenchymal stromal cells (MSCs) can provide paracrine factors that repair damage caused by ischemic injury, and oligodendrocyte progenitor cell (OPC) grafts give dramatic functional recovery from spinal cord injury. These studies have progressed to clinical trials, including human embryonic stem cell (hESC)-derived OPCs for spinal cord repair. However, ESC-derived allografts are less than optimal, and we need to identify a more appropriate donor graft population. The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts. Further clarifying how cell reprogramming works may lead to more efficient direct reprogram approaches, and possibly in vivo reprogramming, in order to promote brain and spinal cord repair. Full article
(This article belongs to the Special Issue Myelin Repair)
Figures

Open AccessReview Repair of the Peripheral Nerve—Remyelination that Works
Brain Sci. 2013, 3(3), 1182-1197; doi:10.3390/brainsci3031182
Received: 24 June 2013 / Revised: 7 July 2013 / Accepted: 19 July 2013 / Published: 2 August 2013
Cited by 12 | PDF Full-text (603 KB) | HTML Full-text | XML Full-text
Abstract
In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created
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In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created by this cell type is essential for the outcome of the repair process. The review starts with a description of the current state of knowledge about the initial events after injury, followed by Wallerian degeneration, and subsequent regeneration. The importance of surgical repair, carried out as soon as possible to increase the chances of a good outcome, is emphasized throughout the review. The review concludes by describing the target re-innervation, which today is one of the most serious problems for nerve regeneration. It is clear, compiling this data, that even though regeneration of the peripheral nervous system is possible, more research in this area is needed in order to perfect the outcome. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessReview Astrocyte Regulation of CNS Inflammation and Remyelination
Brain Sci. 2013, 3(3), 1109-1127; doi:10.3390/brainsci3031109
Received: 15 May 2013 / Revised: 12 July 2013 / Accepted: 12 July 2013 / Published: 22 July 2013
Cited by 15 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of
[...] Read more.
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary. Full article
(This article belongs to the Special Issue Myelin Repair)

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