What if myelin sheath is damaged

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Demyelinating disease: What can you do about it? Products and services. What types of demyelinating disease affect the central nervous system, and what can you do about them? Answer From Jerry W. With Jerry W. As many as 20 percent of people are left with significant disability. Once a diagnosis is made, your doctor can begin discussing the most appropriate treatment for you. There are a number of different FDA-approved preventive treatments for reducing the frequency and severity of MS symptoms, including:.

Steroids are also prescribed for flare-ups or exacerbations. Recent research also suggests that it may be possible to repair the myelin if people have enough surviving oligodendrocyte cells , which wrap around the nerve cells, to begin making new myelin. Sometimes optic neuritis symptoms will improve on their own, but your doctor may prescribe steroids to address the inflammation.

Treatment may be given to address symptoms and reduce inflammation, and to address any infections that might be present. Possible treatments include:. Your doctor may prescribe corticosteroids or immunosuppressants to reduce symptoms. Another possible option is a process called plasmapheresis , which removes certain antibodies from your blood that may be contributing to the symptoms.

Intravenous steroids like methylprednisolone or oral steroids can help reduce the inflammation caused by ADEM. Plasmapheresis may also be an option with severe cases of this condition. One effective treatment for childhood ALD is hematopoietic stem cell transplant, which is a bone marrow transplant. Some people may also take seizure medications or go to physical therapy to help with muscle spasms and weakness.

The most commonly used treatments include glucocorticoids, intravenous immunoglobulin IVIg , and plasma exchange therapy to help modulate the immune system. Physiotherapy might help you build or maintain muscle strength and function, so you can be as mobile as possible.

Ongoing research, including research into stem cell therapies, may eventually bear fruit in the form of new effective treatments for a variety of disorders that affect the myelin covering of nerve cells. In the meantime, communicating with your doctor about your symptoms, using strategies to help with your daily activities, and reaching out for support are good ways to manage your needs.

A recent study showed the promise of remyelination, which could help reverse some of the damage done to the body by multiple sclerosis. Researchers say the destruction of these sheaths causes multiple sclerosis symptoms. Glial cells play an essential role in the formation of normal nodes of Ranvier with their typical nodal Na v and paranodal K v channel distribution. As it has been reviewed by Schafer and Rasband , there are similarities in the contribution of glial cells in node formation between the CNS and PNS.

Paranode is the adjacent segment to the node of Ranvier where myelin loops provide an anchor by tethering the myelin to the axonal membrane Poliak et al.

Evidence has established a determining role for paranodal axo-oligodendrocyte junction in precise localization of ion channels into specialized domains of myelinated axons Barres et al. Caspr is critical for the establishment of axo-glia junction in myelinated fibers through its interactions with contactin and NF Lyons and Talbot, Caspr deficiency results in disruption of the paranodal region and aberrant distribution of ion channels along the axons Kiernan et al.

As ion channel clustering evolves, shaker type Kv1. This process is an energy dependent mechanism and is essential for rapid and repetitive axonal firing. Similarities exist between the molecular organization of nodes and the axon initial segment; however, while myelin is crucial for the proper molecular organization of nodes, the axon initial segment appears to be intrinsically organized by the neuron Dzhashiashvili et al.

Evidence from our group and others have shown that demyelination due to injury and disease results in disruption of the precise nodal organization causing axonal dysfunction Davis et al. Additionally, myelination provides extrinsic trophic signals, which influence the normal maturation, maintenance, and long-term survival of axons White et al.

Structural and functional importance of nodal organization will be discussed in subsequent sections. Demyelination is damage or loss of the myelin sheath around axons. It is mainly a consequence of oligodendroglia cell death that can occur through multiple mechanisms depending on the type of disease or injury, including genetic defects, infectious agents, autoimmune reactions, trauma, and some by unknown mechanisms Zimmerman, ; Popescu and Lucchinetti, ; Kutzelnigg and Lassmann, Several genetic disorders exist that can cause defects in myelin through improper myelination and myelin maintenance or progressive demyelination over time.

Charcot-Marie-Tooth disease CMT , Alexander disease, and Krabbe disease are examples of the many known genetic diseases characterized by axonal demyelination or dysmyelination Ida et al. The early stages of MS involve relapsing-remitting where patient experience demyelination associated with loss of function i.

In the progressive stages of MS, irreversible functional deficit occurs which has been associated with progressive loss of axons and neurons Kurtzke et al. Degeneration of chronically demyelinated axons is now considered to be a major contributor to the permanent neurological disability that MS patients eventually endure Saito et al. Demyelination can also occur through traumatic injury. In the chronically injured spinal cord, there is varying degree of demyelination and dysmyelination in the subpial rim surrounding the lesion site Nashmi and Fehlings, Following SCI, some axons and oligodendrocytes are initially lost through necrosis due to mechanical injury.

As injury evolves, progressive loss of oligodendrocytes occurs through apoptosis and autophagy that results in demyelination of injured spared axons Abe et al. However, this remyelination attempt is often limited and inadequate due to changes to the post-injury environment Barnabe-Heider et al. Therapeutic strategies aimed at promoting remyelination have demonstrated the potential to promote axonal sparing and limit progressive axonal dieback in chronic SCI Karimi-Abdolrezaee et al.

Animal models of demyelinating disease such as MS provide invaluable tools to study myelin—axon interactions and understand the pathological effects of demyelination on axonal integrity and function. Here, we will primarily focus on the effects of demyelination on axons in models of MS and SCI, however, many of the details provided here also correlate with other findings in the literature in other demyelinating conditions.

Loss of myelin sheath causes aberrant distribution of ion channels, where Na v channels diffuse away from the nodes and redistribute across the axonal surface Waxman et al. Additionally, there appears to be an overall increase in the expression of Na v channels in chronically demyelinated axons Bostock and Sears, ; Foster et al.

Following experimental autoimmune encephalomyelitis EAE , Na v 1. Inhibition of sodium channels and NCX has been shown to prevent axonal degeneration Rosenberg et al. Lack of ATP in chronically demyelinated axons is thought to render axons vulnerable to cellular death over time Stys, Axonal degeneration caused by sodium influx is thought to be mainly mediated through Na v 1. Importantly, in chronic lesions of MS, Na v 1.

Evidence shows that demyelinated axons are more susceptible to axonal injury than dysmyelinated axons, which may be explained by the altered expression of Na v 1. Because Na v 1. These studies revealed aberrant localization and increased expression of both Kv1.

Using sucrose gap recording of spinal cord monophasic compound action potentials CAP , we demonstrated that Shiverer spinal cord axons have significantly lower CAP amplitude and area compared to wild-type counterparts Sinha et al.

These studies collectively demonstrate the pivotal role of axo-myelin interactions in ion channels distributions and functions and more importantly on axonal physiology. Axonal transport shuttles critical cell body-derived components back and forth between the soma and axon and across synapses in neurons Millecamps and Julien, Dysfunction of axonal transport causes neuronal homeostasis imbalance and as a result makes axons more susceptible to axonal degeneration.

Accumulation of APP is known as; an early marker of injury in MS patients and is believed to accumulate due to lack of axonal transport following injury Ferguson et al. Oligodendrocytes and their myelin sheath are critical in regulating slow and fast anterograde transport rates Kirkpatrick et al. Reduced fast axonal transport can cause degeneration in distal parts of the axons as observed in X-linked spastic paraplegia type 2, which is caused by a mutation of the PLP1 gene, a major protein of the myelin sheath.

Absence of PLP causes swelling of axons and deficits in retrograde and anterograde transport Griffiths et al. In both humans and mice, absence of PLP causes selective axonal degeneration of long tracts including the fasciculus gracilis and distal corticospinal tracts Garbem et al. Conversely, Shiverer mice, lacking MBP, demonstrate a significant increase in slow axonal transport associated with increased density and instability of microtubules in axons Kirkpatrick et al.

Demyelination-induced defects in axonal transport has been also detected in MS models Lin et al. Studies in an EAE model of optic neuritis in rats suggest that the extent of disruption in axonal transport appear to be correlated with the severity of inflammation, demyelination, and axonal injury Lin et al. Live imaging of individual axonal organelles in the spinal cord of mice with acute EAE revealed that the anterograde and retrograde transport of mitochondria and peroxisomes were markedly reduced in spinal axons, which passed through the lesion Sorbara et al.

Transport deficits were shown to occur prior to any marked alteration of microtubule tracks Sorbara et al. Dysfunction of axonal transport recovers within days following insult. However, in chronic MS lesions, transport deficits were apparent resulting in lack of distal organelle supply Sorbara et al. In chronic MS models, anterograde transport from the soma to the synapses appears to be considerably affected resulting in reduced organelle transport from cell body to the axonal terminal at synapses Sorbara et al.

The majority of white matter tract axons were entirely enwrapped by myelin; therefore, it is likely that axons cannot obtain proper nutrient support from their external environment on their own and require metabolic support from glial cells Saab et al.

It is currently unknown whether glucose transporters are present at the node of Ranvier Saab et al. Astrocytes were further connected to the blood—brain-barrier and to the nutritive support by brain capillaries Karimi-Abdolrezaee and Billakanti, Oligodendrocytes, expressing connexin Cx 47, were coupled to astrocytes, expressing Cx30, through gap-junctions Tress et al.

This evidence suggests that myelination has a dual role in supporting the metabolic activity of neurons by saving energy of axons through saltatory conduction and providing nutrients to neurons.

Ensheathment of axons by oligodendrocytes are shown to drastically diminish the ATP consumption of neurons by reducing the energy required by axons to transmit signals over long distances through saltatory conduction Barron et al. However, is it important to take into consideration that the metabolic cost of myelin synthesis and maintenance might be higher than the saved energy Harris and Attwell, Nonetheless, myelin does save the amount of energy required in neurons by decreasing the energy expenditure required to maintain its resting membrane potential and to propagate signals Saab et al.

Following demyelination, there is an overall increased demand for ATP Andrews et al. Shiverer mice exhibit a significant change in the density and activity of mitochondria in their axons in comparison to wild type animals Andrews et al.

Similarly, unmyelinated segments of retinal ganglion cell axons in the lamina cribrosa also show increased metabolic activity in comparison to myelinated segments Bristow et al. Increased metabolism requirements for demyelinated axons may make these axons more susceptible to death through disease mechanisms such as inflammation Millecamps and Julien, Mitochondria are the major source of axonal ATP and play a critical role in apoptosis, reactive oxygen species generation and calcium buffering Sheng and Cai, Two separate populations of mitochondria exist in myelinated axons, stationary and motile mitochondria.

The majority of mitochondria are located throughout the axons in stationary sites where multiple mitochondria reside Ohno et al. These stationary mitochondria do not translocate and usually vary in length but typically contain the same diameter throughout the population Ohno et al.

A separate population of relatively small but motile mitochondria also exist which translocate in both anterograde and retrograde directions Detmer and Chan, These motile mitochondria are produced in the cell body, and can stop within stationary sites. They are essential for the turnover and redistribution of mitochondria and have been shown to fuse with or bud from stationary mitochondria Detmer and Chan, ; Berman et al.

The rate of transport and docking of these motile mitochondria can be influenced by axonal metabolic demand, such as increases in axonal firing Ohno et al. Recent evidence has shed some light onto the changes that occur to mitochondria in the acute stages of demyelination. Following demyelination there is an overall increased demand for ATP mainly due to changes in ionic homeostasis Barron et al. Moreover, the size of stationary sites and the speed of mitochondrial transport is increased in demyelinated axons Kiryu-Seo et al.

In vitro studies on myelinated rat dorsal root ganglion DRG axons showed 2. This response is shown to be an axonal response to the increased ATP demand of demyelinated axons mediated, at least partially, through activating transcription factor 3 Kiryu-Seo et al. Increased volume of mitochondria at these stationary sites are shown to be a protective response by demyelinated axons mediated through syntaphilin, a protein, which tethers mitochondria to microtubules at stationary sites Ohno et al.

Chronically demyelinated axons exhibit increased expression of syntaphilin Mahad et al. Demyelinated axons deficient in syntaphilin degenerate at a significantly greater rate than wild type axons associated with smaller increases in stationary mitochondrial volume indicating the importance of mitochondrial migration to these stationary sites Ohno et al.

In summary, increasing mitochondrial stationary site size is important in protecting neurons from degeneration following CNS demyelination Kiryu-Seo et al. Despite this protective response from axons, mitochondrial function appears to be limited in chronically demyelinated lesions of MS Sheng and Cai, Following demyelination, changes to the energy balance in axons and dysfunctions of axonal mitochondria contribute to degeneration of chronically demyelinated axons Sheng and Cai, There appears to be an overall decrease in the ability of neurons to produce ATP through their mitochondria Dutta et al.

In postmortem MS tissues, there was a decreased expression of mitochondrial electron transport chain genes which was associated with decreased ability of mitochondria to exchange electrons in respiratory chain complex I, III Dutta et al. This decrease in respiration was later shown to be mediated through deletion of mitochondrial DNA in axons Campbell et al.

These data suggest that mitochondria in the chronically demyelinated axons have a reduced ability to produce ATP, which can contribute to the axonal degeneration over time. However, the extent and quality of remyelination is limited following injury resulting in limited reorganization of nodes of Ranvier and continued axonal dysfunction Nashmi et al.

In rat compressive chronic SCI, we found considerable number of chronically injured axons in the rim of white matter that exhibited aberrant distribution of Kv1. Additionally, electron micrographs of the injured white matter showed that the spontaneous remyelination after SCI is suboptimal and incomplete as the newly formed myelin around the injured axons is thinner than normally myelinated axons Nashmi and Fehlings, ; Karimi-Abdolrezaee et al.

Considerable evidence over the past years has uncovered that failure of the injured and diseased spinal cord for adequate remyelination is attributed to multiple factors that include 1 the limited replacement of myelinating oligodendrocytes by spinal cord progenitor cells Mothe and Tator, ; Meletis et al.

In the following sections, we will discuss endogenous mechanisms of remyelination and the role of injury microenvironment in modulating the replacement of oligodendrocytes and axonal remyelination. Spinal cord injury results in loss of oligodendrocyte population acutely due to necrosis caused by the primary tissue damage Almad et al. However, oligodendrocyte cell loss continues progressively through apoptosis-mediated cell death at subacute and chronic stages of SCI Casha et al.

Interestingly, apoptotic oligodendrocyte death is also observed chronically along the long fiber tracts as a consequence of axonal degeneration and loss of trophic support from axons Crowe et al. Similar process has been observed chronically in primate models of contusive SCI Crowe et al.

Multiple secondary injury mechanisms contribute to oligodendrocyte loss in SCI including digestion by proteolytic enzymes released from damaged cells and toxic blood components Juliet et al. Despite extensive cell death, new oligodendrocytes form and remyelination occurs spontaneously following SCI and demyelinating CNS diseases Chari, ; Zawadzka et al.

Mature oligodendrocytes are post-mitotic and unable to contribute to cell renewal Keirstead and Blakemore, However, the spinal cord harbors a population of adult OPCs that contribute to oligodendrocyte replacement following injury McTigue et al.

Recent findings have shown that resident adult spinal cord OPCs become activated, and change their gene transcription pattern resembling immature OPCs Moyon et al. OPCs differentiate into myelinating oligodendrocytes and remyelinate spared axons following demyelination Gensert and Goldman, ; McTigue et al.

In addition to OPCs, the spinal cord also contains a population of endogenous NPCs, which is known to contribute to oligodendrocyte replacement following injury Horky et al. These NPCs exist in the ependymal layer of the intact spinal cord Weiss et al. In adulthood and under normal conditions, NPCs are latent and their activity is mainly to maintain their own population through self-renewal Meletis et al.

However, upon injury, they become activated and migrate to the site of injury where they can generate new glial cells Horner et al. Studies by our group and others have demonstrated that activated NPCs predominantly differentiate into astrocytes after SCI, with limited number differentiating into new oligodendrocytes Mothe and Tator, ; Meletis et al.

Recent studies have shown that limited ability of NPCs for oligodendrocyte differentiation in SCI milieu may be attributed to unavailability, or modified expression of essential growth factors for oligodendrocyte development Karimi-Abdolrezaee et al. Several studies have addressed this possibility by administering growth factors to optimize the post-SCI microenvironment to support survival and differentiation of transplanted and endogenous NPCs into oligodendrocytes as well as remyelination Karimi-Abdolrezaee et al.

Importantly, transplanted NPCs were able to survive and integrate within the host tissue and differentiate into mature myelinating oligodendrocytes and remyelinated axons Karimi-Abdolrezaee et al. In vivo delivery of these growth factors into animal models of contusive SCI was associated with increased proliferation in ependymal layer where NPCs reside. However, despite increased proliferative activity, no significant change in oligodendrogenesis were seen, which could be due to the lack of PDGF-AA in this growth factor regimen Kojima and Tator, , PDGF-AA promotes the proliferation of glial progenitor cells and can trigger differentiation and survival of newly formed oligodendrocytes Raff et al.

However, these FGF receptor null animals demonstrated defective myelin thickening during postnatal period and remained defective throughout their adulthood Furusho et al. This evidence suggests that FGF signaling can regulate myelin sheath thickness Furusho et al.

Mash1, a transcription factor known to promote neural differentiation, have also been implicated in endogenous oligodendrocyte differentiation Parras et al. Retroviral induction of Mash1 expression in endogenous spinal cord NPCs following SCI resulted in increased oligodendrocyte differentiation and formation of new oligodendrocyte progenitor cells following a complete transection rat model of SCI.

Neuregulin-1 Nrg-1 is another growth factor known to promote OPCs survival, migration, and differentiation into mature myelinating oligodendrocytes Vartanian et al. Nrg-1 is known to play essential roles in oligodendrocyte and SC myelination Brinkmann et al.

Our group has recently demonstrated that the rapid and long lasting downregulation of Nrg-1 following contusive SCI is an underlying cause of inadequate oligodendrocyte differentiation Gauthier et al. Restoring the reduced levels of Nrg-1 in the injured spinal cord enhanced tissue preservation, oligodendrocyte differentiation of spinal cord NPCs, and increased oligodendrocyte and axonal survival following SCI Gauthier et al. Collectively, these studies show the necessity of micro-environmental optimizations in order to improve endogenous and exogenous replacement of oligodendrocytes and axon remyelination following SCI.

Current evidence shows that remyelination is additionally limited by inhibitory modifications in the post-SCI niche caused by secondary injury mechanisms particularly in chronic SCI Larsen et al. Newly formed oligodendrocytes often fail to fully ensheath and myelinate the injured spared axons following injury resulting in incomplete remyelination Salgado-Ceballos et al. These inhibitory signals are primarily associated with myelin debris, activated glial cells, and infiltrating leukocytes following injury Ji et al.

Presence of myelin debris and insufficient clearance by microglia and macrophages contributes to incomplete remyelination by inhibiting OPCs differentiation and maturation in vitro and in vivo Kotter et al. Recent in vitro studies by Plemel et al. This was demonstrated by a significant decrease in the number of mature oligodendrocytes and was accompanied by increased expression of two proteins, namely inhibitor of differentiation ID 2 and ID4 that are known to block oligodendrocyte maturation Plemel et al.

It has been shown that myelin clearance and remyelination become less sufficient with aging due to changes in macrophage secretory and phagocytic activity Shields et al. Myelin debris is a potent inhibitory component of injured spinal cord that impairs regeneration and remyelination. Thus, proper myelin clearance is an important step for remyelination process Kotter et al.

Dysregulation of Wnt signaling in OPCs also inhibits myelination during development and repair Fancy et al. Wnt signaling is activated in differentiating OPCs following chemically induced demyelination and in samples from MS patients Fancy et al. Following demyelination, upregulation of T-cell factor 4 tcf4 , a Wnt pathway mediator, is significantly upregulated in differentiating OPCs and inhibit oligodendrocyte maturation and myelination Fancy et al. Its level increases significantly after SCI, reaching its peak at one week following injury Kaneko et al.

Increased expression of Sema3A has also been observed in MS and experimental demyelination models Piaton et al. Sema3A overexpression delays recruitment of OPCs to the demyelination site through a chemo-repulsive mechanism Piaton et al. Use of Sema3A inhibitor improved tissue preservation, remyelination and functional recovery following SCI Kaneko et al. We will discuss recent studies on the role of resident glial cells and peripherally recruited immune cells in modulating oligodendrocyte replacement and remyelination following CNS injury.

Astrocytes play critical role in several aspects of myelination in pathologic CNS including clearance of myelin debris, modulating the activity of oligodendrocytes, myelin maintenance, and renewal Sorensen et al. Using a cuprizone model of rodent demyelination, Skripuletz et al.

Intercellular connections between astrocytes and oligodendrocytes are critical for the proper physiology of oligodendrocytes. While there are no gap junctions between oligodendrocytes themselves, they are connected to astrocytes through gap junctions, which make oligodendrocytes indirectly interconnected Nagy et al. Evidence shows that gap junctions are essential for proper myelin physiology in the CNS Menichella et al. Four different types of connexins have been identified in oligodendrocytes Cx29, 32, 45, Cx29, Cx32, and Cx47 are known to be expressed by oligodendrocytes that in conjunction with Cx26, 30, 43 on astrocytes, form the astrocyte-oligodendrocyte gap junction complex Scherer et al.

Double knockout mice models lacking Cx47 and Cx32 die postnatally due to severe apoptotic oligodendrocyte death, hypomyelination, and axonal degeneration Menichella et al. This evidence suggests a critical role for astrocyte and oligodendrocytes inter-cellular signaling in myelin physiology. Astrocytes provide trophic support to oligodendrocytes by producing growth factors. In an ethidium bromide EB induced rat model of spinal cord demyelination, Talbott et al.

Astrocytes are known to produce PDGF and LIF, which are supportive for oligodendrocyte survival at progenitor and mature stages, respectively Barres et al. While supportive of myelination in the normal CNS, astrocytes can play detrimental roles in CNS remyelination following pathology Rosen et al. Astrocytes contribute substantially to the extracellular matrix of the CNS.

Following injury, they are activated and form a glial scar, which is inhibitory to the repair and regeneration of the CNS. The inhibitory influence of scar is mediated mainly through chondroitin sulfate proteoglycans CSPGs , which have known inhibitory effects on axonal regeneration, axonal conduction, remyelination, and cellular therapies in SCI Massey et al.

Our recent evidence shows that CSPGs inhibit the ability of NPCs to proliferate, spread their cell processes, survive and differentiate into oligodendrocytes Dyck et al. The detrimental effect of CSPGs upregulation by astrocytes is also observed in MS lesion where the CSPGs aggrecan, neurocan, and versican as well as hyaluronan accumulate at the borders of active demyelinating lesions Back et al. In addition to the inhibitory ECM produced by astrocytes, reactive astrocytes can also be detrimental to remyelination in demyelinated CNS through the secretion of Endothelin-1 Hammond et al.

Endothelin-1 is shown to inhibit the differentiation of OPCs into mature myelinating oligodendrocytes through the activation of Notch signaling.

Taken together, these data demonstrate the complex role of astrocytes in the CNS. The presence of astrocytes is required to produce healthy myelin, however, the detrimental effects of activated astrocytes and their production of inhibitory ECM molecules following injury limits the ability of the CNS in self-repair and axon remyelination.

Thus, developing interventions to moderate the inhibitory effects of scar-associated molecules is a vital therapeutic strategy for CNS repair and remyelination following injury. Emerging evidence indicates that macrophages and microglia also play critical roles in modulating demyelination and remyelination through their antigen presenting ability and production of cytokines, chemokines and growth factors for review see Gordon, ; Mosser, ; Martinez et al.

This time window was closely correlated with a regenerative stage at which OPCs were recruited to the site of lesion, and differentiated into mature myelinating oligodendrocytes Miron et al. Adding M2 conditioned media into OPCs cultures increased oligodendrocyte differentiation and maturation Miron et al. Selective depletion of M1 macrophages by intralesional injection of gadolinium chloride reduced the proliferation rate of OPCs without affecting their migration and remyelination capacity.

Interestingly, in a rat model of lysolecithin demyelination, M2 depletion was associated with delayed oligodendrocyte differentiation and nodal reconstruction Miron et al.

Interestingly, the extent of SC remyelination remained unaffected Kotter et al. Of note, these studies also revealed that the timing of macrophages response is a key factor as the early presence of the macrophages was important for remyelination while delayed macrophage depletion did not impair remyelination Kotter et al.

Several mechanisms have been proposed for the positive role of macrophages in remyelination. However, recent studies by Kotter et al. Altogether, evidence indicates that the type of immune response is a determining factor that can promote or inhibit remyelination in demyelinating CNS lesions as reviewed by Mosser, ; Wee Yong, Accordingly, targeted immunomodulatory strategies rather than complete anti-inflammatory treatments appears to be a more effective strategy for promoting remyelination in autoimmune demyelinating conditions such as MS.

Further research was needed to elucidate the mechanisms involved in immune response after demyelinating CNS conditions and the factors that promote remyelination Jackson et al. Following SCI or demyelination, endogenous SCs invade the injury site and contribute to remyelinating the demyelinated axons Blakemore, ; Bunge et al. SCs enter through dorsal funiculi via dorsal root entry zone or lateral funiculi from the rootlets that become adhered to the lateral spinal cord after injury Jasmin et al.

In chemical models of demyelination in rodents, remyelination by endogenous SCs and oligodendrocytes progress simultaneously and fully myelinate demyelinated axons by 4 weeks following the insult. However, the extent of oligodendrocytes remyelination is smaller when compare to peripheral myelin formed by SCs and is restricted to the edges of the lesion Blakemore, The limited degree of oligodendrocyte remyelination has been attributed to the absence of astrocytes in chemically demyelinated lesions, as oligodendrocytes are dependent on astrocytes for remyelination Blakemore, ; Blakemore and Patterson, Entry of SCs to the injured spinal cord is normally limited by glia limitans formed by astrocytes.

Following insult, SCs invade the spinal cord through the regions where glia limitans is disrupted. When the glial limitans is re-established by astrocytes, SC invasion becomes progressively limited Blakemore, Interestingly, studies have shown that oligodendrocytes gradually replace SCs in remyelinated axons and the transition from peripheral to central myelination occurs without any loss of function Jasmin et al.

However, other studies showed that SCs persist even chronically following SCI and continue myelinating axons Hill et al. Subsequent studies investigated the transition from SCs to oligodendrocytes remyelination and found no change in SC myelination despite increasing oligodendrocyte myelination in EB and radiation X-EB demyelination model Gilson and Blakemore, There is also evidence that transplantation of OECs, SCs, and bone marrow stromal cells can promote migration of SCs from dorsal roots into the injury site Hill et al.

Therefore; enhanced remyelination or other beneficial effects observed after cell transplantation can be partially attributed to migrating SCs particularly in studies with poor survival of transplanted cells. This evidence suggests that SCs serve as emergency responders and protect demyelinated spinal cord axons at the time when oligodendrocytes are unable to remyelinate efficiently.

Cell transplantation in particular has shown promising results in enhancing SCI repair through multiple mechanisms including cell replacement, trophic support, immunomodulation, and remyelination Ogawa et al. List of selected cell therapies for promoting remyelination following spinal cord injury SCI and multiple sclerosis MS. Potential of transplanting NPCs or glial progenitor cells in promoting remyelination has been explored in a wide variety of pathological conditions such as SCI, genetically myelin deficient rodent models, and MS Karimi-Abdolrezaee et al.

These studies have collectively demonstrated the ability of transplanted NPCs to differentiate into myelinating oligodendrocytes and ensheath demyelinated axons. Our studies in mutant Shiverer mice and rat SCI revealed that NPC-derived oligodendrocytes integrate with demyelinated and dysmyelinated axons and successfully remyelinate them Karimi-Abdolrezaee et al.

When we transplanted brain-derived NPCs into the spinal cord of subacutely injured rats, we found that survival and oligodendrocyte differentiation of NPCs was limited in the injury microenvironment Karimi-Abdolrezaee et al. Importantly, in adult Shiverer mice transplanted with NPC, we found evidence of myelination and normal reconstruction of the node of Ranvier in chronically dysmyelinated axons Eftekharpour et al.

Of note, in these studies, transplantation of NPCs resulted in improved locomotor recovery evident by significant improvements in BBB and grid walking test as well as foot print analysis Karimi-Abdolrezaee et al. Confocal immunostaining of Kv1. Caspr blue immunostaining was used to identify the paranodal area.

Note that the processes of YFP-labeled oligodendrocytes avoid the nodal region U. From Eftekharpour et al. Subsequent studies by Windrem et al. In this study, transplanted cells successfully differentiated into myelinating oligodendrocyte and functionally myelinated the dysmyelinated host axons in forebrain and brainstem Windrem et al.

In agreement with our studies, immunohistological and electrophysiological evidence revealed reconstruction of the node of Ranvier in transplanted neonatal Shiverer mice and restoration of transcallosal conduction velocity Windrem et al.

Moreover, transplanted mice showed increased lifespan and decreased seizure rate, which is frequently seen in Shiverer mice Windrem et al. Collectively, these studies provided proof-of-concept evidence that NPC-derived oligodendrocytes can functionally remyelinate chronically demyelinated axons in SCI and demyelinating lesions.

Recent studies have provided further evidence that implicates remyelination as a key mechanism for neurological improvement observed after transplantation of NPCs in models of SCI Yasuda et al. Yasuda et al. Neuroanatomical, functional, and electrophysiological analyses demonstrated better outcomes in the injured mice transplanted with wild-type NPCs compared to the mice that received Shiverer NPCs Yasuda et al.

This work and similar study by Hawryluk et al. As mentioned earlier, in the post-SCI microenvironment, transplanted stem cells exhibit limited capacity for survival and migration and they primarily differentiate into astrocytes at the expense of oligodendrocytes and neurons Hofstetter et al.

Their findings may have implications for disease associated with myelin loss, like multiple sclerosis MS. The reason? These regenerated axons are not myelinated. In this new study, published in Neuron , He explains why those axons fail to remyelinate after injury. In the adult brain, myelination is carried out by cells called oligodendrocyte precursor cells OPCs. Second, inflammatory cells in the injured nerves interfere with another step of OPC differentiation.

After testing a set of available compounds, co-first author Jing Wang, PhD, of the He lab, discovered that montelukast, an anti-inflammatory used for treatment of asthma and seasonal allergies, blocked development or action of GPR Some axon remyelination was restored but only in about approximately 15 percent of treated nerve cells. However, myelination rates were boosted significantly after removing immune cells, called microglia, from the damaged nerve cells with a drug called PLX By itself, PLX increased remyelination in 21 percent of axons.

In combination with montelukast, the combination lead to remyelination in about 60 percent of damaged axons.