Mediators of Oligodendrocyte Differentiation During Remyelination

Abstract

Myelin, a dielectric sheath that wraps large axons in the central and peripheral nervous systems, is essential for proper conductance of axon potentials. In multiple sclerosis (MS), autoimmune-mediated damage to myelin within the central nervous system (CNS) leads to progressive disability primarily due to limited endogenous repair of demyelination with associated axonal pathology. While treatments are available to limit demyelination, no treatments are available to promote myelin repair. Studies examining the molecular mechanisms that promote remyelination are therefore essential for identifying therapeutic targets to promote myelin repair and thereby limit disability in MS. Here, we present our current understanding of the critical extracellular and intracellular pathways that regulate the remyelinating capabilities of oligodendrocyte precursor cells (OPCs) within the adult CNS.

Introduction

Multiple sclerosis (MS) is characterized by progressive clinical decline due to axonal loss from chronic demyelination [1]. Although for many patients early disease is characterized by remyelination and recovery of function, eventually remyelination becomes limited and ultimately fails, for unclear reasons, leading to worsening disability [2]. Indeed, acutely injured axons may be found within demyelinated and actively demyelinating lesions, suggesting an intimate association between the mechanisms leading to myelin and axonal injury [3]. As oligodendrocyte precursor cells (OPCs) can be detected in MS lesions, it would seem that the endogenous repair mechanisms that normally respond to myelin damage become defective throughout the course of disease. Thus, there is great interest in understanding these mechanisms in order to identify reasons for failure and to develop therapies that promote the proliferation, migration and/or differentiation of OPCs in areas where demyelinated axons are at risk for further damage. Animal studies examining remyelination utilize a variety of approaches, which each highlight essential aspects of OPC biology. Thus, in murine models white matter damage is caused by induction of myelin-reactive immune cells via immunization or infection with mouse hepatitis virus (MHV), the latter of which leads to an acute encephalitis followed by a chronic demyelinating phase due to viral persistence within oligodendrocytes, or via use of ingestible or injectable toxins, such as cuprizone or lysolecthin, respectively, which induce apoptosis specifically in oligodendrocytes [4–5]. Findings in these models have been difficult to validate in MS patients primarily because human studies of demyelinated lesions are generally limited to analyses of postmortem tissue in patients with longstanding, progressive disease [2]. Many of these samples do not exhibit the dynamic OPC behaviors observed in animal models due to the physical and chemical barrier presented by astrogliosis. In this review, we will briefly outline the molecular pathways involved in regulation of remyelination that have been identified using animal experimentation and, where data are available, in validative studies performed using human tissues. The studies published so far provide hope that as critical myelin repair mechanisms are unraveled in the adult brain, there will be demonstrable targets for the correction of these processes in MS.

Oligodendrocyte differentiation during remyelination

Remyelination is the regeneration of an axon’s myelin sheath that has been damaged in many diseases such as MS. In general, the cellular mechanisms that mediate remyelination are a recapitulation of processes that occur during development. However, certain extracellular signaling molecules, such as chemokines, appear to function similarly during developmental myelination and remyelination. In the postnatal and adult brain, oligodendrocyte lineage cells migrate from the subventricular zone (SVZ) to the developing white matter where they stop proliferating, differentiate and myelinate axons [6–8]. Similar events have been shown to occur during remyelinating phases in mouse models of demyelination [5; 9–11]. For example, in both the lysolecithin-induced focal demyelination model, where toxin in directly injected into white matter areas, and in the cuprizone intoxication model, in which ingestion of copper chelator leads to complete demyelination of the corpus callosum, chondroitin sulphate proteoglycan positive (NG2+) cells are recruited to areas of demyelination from the subventricular zone (SVZ) [5; 12–13]. These cells differentiate and become oligodendrocytes that express myelin proteins in a sequential manner such that proteolipid protein (PLP), myelin basic protein (MBP) and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) are expressed within five days of toxin cessation, whereas myelin oligodendrocyte glycoprotein (MOG) is not expressed until 8 weeks after the initiation of remyelination [5; 9; 14]. Thus, the mechanisms that mediate remyelination are tightly regulated, orchestrating a specific sequence of events. A variety of proteins have been found to impact on remyelination including cytokines [15–16], chemokines [9; 11; 17–20], signaling molecules, [21–24], growth factors [5; 12; 25], transcription factors [26–28] and microRNA [29–32]. However, the specific role of each of these proteins during remyelination is unknown and simply inhibiting or augmenting expression of any one of these molecules may not be sufficient to promote remyelination in humans. Instead a comprehensive understanding of the functions of these molecules is necessary to devise effective treatment strategies for remyelination failure in MS.

Cytokines

Cytokines mediate inflammatory responses that promote pathogen clearance and prevent excessive tissue damage [33]. However, overproduction of cytokines may lead to excessive inflammation and cell death, as has been observed in peripheral autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease [34–36]. While successful targeting of cytokine production has led to effective treatments for some of these conditions [34–36], in the CNS certain cytokines exhibit critical roles in repair mechanisms. Thus, understanding downstream effects of cytokine signaling pathways in the CNS is essential for creating MS treatments that both prevent damage and promote repair.

Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that signals through TNFR1 and TNFR2, activates two different pathways: one that leads to apoptosis via death domain mediated caspase activation (TNFR1) and another that activates survival and protective pathways via nuclear factor kappa β (NFκβ) (TNFR1 and TNFR2) [37–38]. As TNFR1 binds the soluble form of TNF-α while TNFR2 binds the membrane bound form, the downstream effects of TNF-α signaling depend on the proximity of cellular sources of both ligand and receptor. Compared to unaffected individuals, MS patients exhibit high levels of TNF-α in both the cerebrospinal fluid and serum, which are positively correlated to severity of lesions [39–41]. In mice with experimental autoimmune encephalitis (EAE) induced by immunization with myelin peptides, overexpression of TNF-α worsens demyelinating disease and administration of anti-TNF-α neutralizing antibodies or receptor fusion proteins is protective [42–47]. Despite these findings, clinical trials with, lenercept, a TNFR1 receptor extracellular domain fused to human IgG1 heavy chain, resulted in increased frequency, duration, and severity of MS exacerbations [48], suggesting alternative roles for TNF-α and/or its receptors that may depend on the disease stage. Studies using mice with targeted deletions of TNF-α or its receptors demonstrate that TNF-α mediates remyelination via TNFR2 signaling. Administration of cuprizone to TNF-α and TNFR2 knockout mice led to a significant delay in remyelination compared with wildtype control mice [15]. The attenuation in remyelination correlated with a reduction in the pool of proliferating oligodendrocyte progenitors and reduced mature oligodendrocytes. Analysis of mice lacking TNFR1 or TNFR2 indicated that TNFR2 is necessary for oligodendrocyte maturation [35]. These data suggests that TNF-α plays a role in CNS repair of myelin and explain the failure of anti-TNF agents to alleviate disease in MS patients.

Interleukin (IL)-1β is a proinflammatory cytokine associated with the pathology of demyelinating disorders such as MS and viral infections of the CNS and is induced during demyelination in animal models [16; 49–50]. Although IL-1β exerts cytotoxic effects on mature oligodendrocytes in vitro [51–52], IL-1β knockout mice do not exhibit differences in the severity of demyelination, the depletion of mature oligodendrocytes or the accumulation of oligodendrocyte progenitors within demyelinating lesions compared to wild-type mice during cuprizone-induced demyelination [16]. However, IL-1β knockout mice fail to adequately remyelinate due to lack of IL-1β–mediated expression of insulin growth factor (IGF)-1 [16; 53]. The expression of IGF-1 message and protein parallels the accumulation and differentiation of oligodendrocyte progenitors within the lesion, which the IL-1β knockout mice do not exhibit [16; 53]. Similar to TNFα, IL-1β has been associated with exacerbating CNS pathology [49; 54]. Conversely, it aids in repair by inducing growth factor production to promote mature oligodendrocyte differentiation and remyelination during a pathological insult within the CNS

Chemokines and MS

Chemokines induce directed chemotaxis in nearby responsive cells, which is necessary to guide immune cells to sites of infection or injury. Many chemokines including CXCL12 and CXCL1 are induced during CNS development and direct the migration and maturation of neural precursor cells [55–57], suggesting that these molecules could mediate migration and differentiation during repair of CNS. Because remyelination failure may be due to either the lack of differentiating signals or the presence of inhibitory signals for OPCs, chemokine neurobiology has become an important area of investigation in studies of remyelination.

CXCL12 (formerly called stromal cell-derived factor (SDF)-1) is a potent leukocyte chemoattractant that controls B-cell lymphopoiesis and hematopoietic stem cell homing to bone marrow via signaling through G-protein-coupled receptor CXCR4 [58]. CXCR4 signaling is conserved in vertebrates, as it controls primordial germ and sensory cell migration in zebrafish [59]. Another CXCL12 receptor is the newly discovered receptor, CXCR7 that primarily acts to regulate CXCR4 activation via sequestration of CXCL12 [60]. Although studies of CXCR7 in the developing brain are limited, there have been some reports that OPCs may express CXCR7 [61]. Freshly isolated neonatal OPCs specifically respond to CXCL12 by directed chemotaxis, however, their maturation into oligodendrocytes is associated with increased and decreased expression of CXCR7 and CXCR4, respectively [61–63]. Indeed, studies using in vivo demyelinating models support the notion that CXCR4 plays an early role in the migration and differentiation of OPCs. In elegant studies by Carbajal et al., (2010), GFP+ neural stem cells (NSCs) introduced into the spinal cords of mice with chronic demyelination due to infection with MHV strain JHMV resulted in their migration, proliferation, and differentiation into mature oligodendrocytes [11]. Administration of anti-CXCL12 neutralizing antibodies or a small molecule inhibitor of CXCR4, but not CXCR7, resulted in a marked attenuation in both the migration and proliferation of the engrafted stem cells. Using the cuprizone model of remyelination, Patel et al., (2010) showed that CXCL12 specifically mediates OPC differentiation into mature, myelinating oligodendrocytes within the corpus callosum [9]. In these studies, antagonism of CXCR4 via pharmalogical blockade or in vivo RNA silencing led to arrest of OPC maturation, preventing expression of myelin proteins [9]. Taken altogether, these data suggest roles for CXCL12 and CXCR4 in the recruitment, proliferation and differentiation of OPCs during remyelination of the adult CNS.

Studies of human CNS tissues indicate that CXCL12 is expressed by endothelial cells and astrocytes (EC) within normal brain and is increased in these and other cells in a variety of diseases including neuroAIDS, stroke and MS [64–67]. Thus, analysis of active MS lesions, which exhibit some amount of remyelination, exhibit increased CXCL12 expression in astrocytes throughout lesion areas and in macrophages within vessels and perivascular cuffs, with low levels of staining on ECs [66]. In chronic MS lesions, however, less CXCL12 was observed with staining detected only within hypertrophic astrocytes near the lesion edge, suggesting a mechanism for loss of remyelination [64]. Because CXCL12 is required to recruit CXCR4+ OPCs for remyelination, but also restricts the entry of CXCR4+ immune cells at EC barriers [66; 68], therapies that promote CXCL12 expression may target both effects of CXCL12 signaling. Several studies suggest IL-1β and TNF-α may induce CXCL12 expression within endothelial cells and astrocytes [69–70] while interferon (IFN)-γ triggers decreased expression of the chemokine [71]. IFN-γ has also been shown to decrease EC expression of CXCR7, which controls levels of abluminal CXCL12 [71]. Thus, anti-cytokine biologicals are likely to impact on remyelination via both direct effects on cytokine signaling and indirect effects on patterns of chemokine expression.

CXCL1/CXCL2/CXCR2

CXCR2 plays a role in inflammation, oligodendroglial biology and myelin disorders [72]. Studies in mouse models of remyelination and of MS lesions demonstrate roles for CXCR2 and its ligands in both inflammation and repair. In active MS plaque lesions, CXCR2 is expressed by proliferating oligodendrocytes and reactive astrocytes, while its ligand, CXCL1, is expressed by activated astrocytes [20; 73], suggesting CXCL1 expression in astrocytes may recruit OPCs to the site of the lesion. However, other studies have shown that CXCR2 activation limits migration of OPCs [57]. In addition, CXCR2 expression has been detected on activated microglia at lesion borders, suggesting alternative functions for CXCR2 in response to injury [74]. Thus, CXCL1/CXCR2 may be involved in both the inflammatory component of MS and in OPC responses during remyelination.

Results in rodent models provide further support for the dual role of this chemokine and its receptor. Lui et al. (2010) detected CXCR2 expression on neutrophils, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes in the CNS [18–19]. CXCR2-positive neutrophils contribute to demyelination in EAE and during cuprizone intoxication [18–19] and systemic injection of a small molecule inhibitor of CXCR2 at the onset of EAE decreased numbers of demyelinated lesions [19]. Bone marrow chimeric mice generated via transfer of CXCR2+/− bone marrow into nonlethally irradiated CXCR2+/+ and CXCR2−/− mice led to more proficient myelin repair in CXCR2−/− versus CXCR2+/+ recipients [19], suggesting that CXCR2 signaling inhibits repair when expressed by radiation insensitive neural cells. In vivo analysis showed that OPCs proliferated earlier in the demyelinated lesions of CXCR2−/− chimeric mice and in greater numbers than in tissues from CXCR2+/+ chimeric animals [18–19]. Demyelinated CNS slice cultures also demonstrated enhanced myelin repair when CXCR2 was blocked with either genetic deletion or neutralizing antibodies. These data suggest that loss of CXCR2 activity both attenuates demyelination and promotes OPC proliferation and differentiation. However, data in other contexts question whether this receptor may be used as a treatment target for demyelinating diseases.

CXCR2 signaling also protects oligodendrocytes and limits demyelination in murine models of virally-induced demyelination [17]. Demyelination induced by JHMV infection induced expression of the chemokines CXCL1 and CXCL2 and their receptor CXCR2 within the spinal cord during the chronic infection phase [17]. CXCR2 antagonism with neutralizing antiserum in this setting delayed clinical recovery and resulted in increased numbers of apoptotic cells mainly within white matter tracts of the spinal cord [17]. Omari et al., (2009) also reported a protective role for CXCR2 during demyelination [75]. In transgenic mice during EAE, overexpression of CXCL1 in astrocytes led to a decrease in clinical severity, a decrease in demyelination and augmentation of remyelination [75]. Lane and colleagues suggest that the protective and pro-apoptotic roles of CXCR2 with regards to oligodendrocytes may be context dependent [17]. Therefore, further studies are necessary to fully determine the role of CXCR2 and its ligands during remyelination before therapeutic targets can be developed.

Toll-like Receptors

Toll-like receptors (TLRs) have well defined roles in innate immunity, but they also influence axonal pathfinding, dorsoventral patterning and hippocampal neurogenesis [76–77]. Recently, TLR-2 and its ligand, hyaluronan was detected in MS lesions and in normal appearing white matter [78–79]. OPC differentiation has been shown to be inhibited by several TLR2 agonists including hyaluronan [79]. These data suggest that TLR signaling could inhibit remyelination in MS and negatively impact on recovery during exacerbation. The development of therapies that inhibit TLR could therefore potentially alleviate failed remyelination in MS.

Growth Factors

Growth factors are defined as biologically active polypeptides that control growth and differentiation of responsive cells. Several of these growth factors were found to influence oligodendrocyte biology both in vitro and in animal models of remyelination. Growth factors have the potential to be a viable treatment option for MS. Transgenic mice overexpressing human epidermal growth factor receptor (hEGFR) exhibit increased lesion repopulation by OPCs with accelerated remyelination and functional recovery following focal demyelination of mouse corpus callosum compared to wild-type mice [5]. EGFR overexpression in SVZ and corpus callosum during early postnatal development also increased progenitor populations and promoted SVZ-to-lesion migration, enhancing oligodendrocyte generation and axonal myelination [5]. These data suggest that EGFR signaling during remyelination is similar to its role during development. EGF levels in the CSF of MS patients with relapsing-remitting or secondary progressive forms were significantly lower than those of nonclinical controls [80], suggesting that insufficient levels of EGF is associated with remyelination failure. Targeting EGF to enhance remyelination may hold promise for MS patients.

Several additional growth factors that are expressed during demyelination and implicated in remyelination include insulin-like growth factor (IGF)-1, platelet derived growth factor (PDGF), and fibroblast growth factor (FGF) [53; 81]. IGF-1 has both a protective and mitogenic role during de/remyelination in the cuprizone model. Thus, mice with targeted deletion of IGF-1 exhibit impairments in OPC proliferation and survival and inadequate remyelination after cuprizone-induced demyelination [53; 82–83]. In addition, in transgenic mice engineered to continuously express IGF-1, oligodendrocytes are protected from apoptosis during cuprizone intoxication [83]. Although a pilot study in which seven MS patients were given recombinant human IGF failed to show any significant differences, the drug was well tolerated [84]. Further studies are ongoing to determine the efficacy of IGF in promoting repair in patients with MS. PDGF and FGF are well-established trophic factors that promote the proliferation and differentiation of NSCs. In mice infected with MHV-A59 to induce focal demyelination of the spinal cord, PDGF and FGF were identified as mitogens regulating the proliferative responses of OPCs [81]. These studies demonstrate that growth factors have impact on all aspects of oligodendrocyte biology and remyelination.

Signaling Pathways

Many factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, but there are several intracellular signaling pathways that possibly mediate remyelination including, Notch-1, LINGO-1 (leucine rich repeat and Ig domain containing NOGO receptor interacting protein 1) and Wnt. Given the extensive recent reviews on Wnt signaling pathways [85–86], it will not be discussed in this review.

LINGO-1 is a protein that is abundantly expressed in the cortex of CNS and has been in implicated in the inhibition of axon regeneration [87]. It also regulates remyelination in the adult CNS by inhibiting oligodendrocyte differentiation. This process is a recapitulation of LINGO-1 function during developmental myelination [88]. Using 3 different animal models of de/remyelination: EAE, cuprizone induced demyelination, and lysophophatidylcholine (LPC) induced demyelination, Mi et al., (2009) demonstrated that LINGO-1 antagonism enhanced OPC differentiation and promoted remyelination of demyelinated axons [88]. Furthermore, LINGO-1 antagonism using monoclonal antibody 1A7 in the EAE model showed improvement in axonal integrity and the formation of new myelin sheath [89]. These data suggest that LINGO-1 antagonism has potential as a therapy for CNS repair of demyelinating disease. Recently, clinical trials have begun that will administer LINGO-1 antagonist BIIB033 to MS patients to determine CNS repair [90]. The efficacy of drug will be assessed via neurological examinations, MS performance scores, and brain magnetic resonance imaging (MRI) scans.

Notch-1 and its ligands are signaling molecules that are involved in gene regulation mechanisms including those that induce neuronal development [21; 91]. Nonmyelinating oligodendrocytes express Notch1 receptors, and neurons/axons express its ligand, Jagged1 or contactin [22; 92]. Binding of Jagged1 to Notch induces expression of the transcription factor Hes5, which blocks the maturation of Notch1-expressing cells, facilitating the migration of OPCs to white-matter tracts of the CNS [92–94]. As development proceeds, downregulation of Jagged1 is associated with the maturation of oligodendrocyte precursors and myelination [94]. In active MS lesions, Jagged1 was detected within reactive astrocytes, whereas Notch1 and Hes5 were found within oligodendrocytes [23]. In contrast, astrocytes in remyelinated areas did not show Jagged1 expression. In addition, outgrowth of processes of human oligodendrocyte cultures was blocked when cells were transfected with Jagged1 [23; 95]. These data suggest that notch-1 may inhibit differentiation of OPCs in order to facilitate their migration to the white matter.

microRNA

MicroRNA are small RNA molecules that function as posttranscriptional regulators of gene function either through translational inhibition or target RNA degradation [31]. These molecules have recently emerged as mediators of many biological functions including the proliferation and differentiation of NPCs [96] and several groups have demonstrated that microRNAs exert roles in remyelination. Junker et al., (2009) created microRNA profiles from active and inactive MS lesions via laser capture microdissection of single cells and showed dysregulation of transcripts such as CD47, which is expressed by apoptotic cells to prevent macrophage phagocytosis, specifically in active lesions [29]. The authors speculated that loss of microRNA-mediated reduction of CD47 could potentially release macrophages from inhibitory control, thereby promoting phagocytosis of myelin. This mechanism may have broad implications for miRNA-regulated macrophage activation in inflammatory diseases [29].

Several studies demonstrate that oligodendrocyte maturation may depend on microRNAs. Dugas et al (2010) showed that conditional deletion of Dicer1, a miRNA-processing enzyme, prevented OPC differentiation in vitro due to the lack of mature miRNAs. Furthermore, microRNA microarray analysis has identified two miRNAs, miRNA-219 and mi-338, necessary for oligodendrocyte differentiation. Inhibition of these specific miRNAs prevents transcription factor induction of OPC maturation [32]. The role of miRNAs in remyelination, however, is unclear as studies have yet to evaluate miRNAs in this context. Future studies will determine whether these small molecules also regulate remyelination.

Transcription Factors

Both myelination and remyelination occur through the activation of myelin protein genes that are induced by various transcription factors. The sequential activation of myelin protein correlates with both activation and inhibition of several transcription factors such as Olig1, Olig2 and Nkx2.2. Olig1 is a basic helix–loop–helix (bHLH) transcription factor expressed by oligodendrocytes in the CNS [97]. This transcription factor is critical for developmental myelination and Olig1−/− mice have a shortened life span [98], resulting from a failure to induce myelin specific gene expression and arrested myelination. Recently, a critical role for Olig1 in repairing demyelinated lesions in the adult CNS has been demonstrated [97]. Olig1 translocates from the cytoplasm to the nucleus in early remyelinating lesions in EAE as well as in oligodendrocyte precursor cells at the edge of MS lesions [97]. Another transcription factor know as SOX10 is part of the SOXE family of transcription factors, which are known to regulate oligodendrocyte fate [99]. SOX10 plays a major role in the promoting terminal oligodendrocyte differentiation and loss of SOX10 activity leads to disruption of oligodendrocyte differentiation [100]. Recent data has shown that Olig1 and SOX10 can complex together to synergistically activate MBP gene transcription [101]. Several transcription factors, such as Mash1 and Tcf4, have been used to identify cells withn the oligodendrocyte lineage but are additionally expressed by multipotent progenitor cells within neurogenic zones [102–103]. Tcf4 has also been demonstrated to function in catenin-dependent Wnt signaling [104].

Olig2 and Nkx2.2 are transcription factors expressed by OPCs and mature oligodendrocytes. Recent studies have revealed the importance of Olig2 for the differentiation of neural progenitor cells into the oligodendroglial lineage [27; 105], while Nkx2.2 regulates the maturation and differentiation of oligodendroglial progenitors [28]. Overexpression of Olig2 induces differentiation of neural stem cells into mature oligodendrocytes in vitro [106] and disruption of Olig2 in vivo leads to a lack of NG2+ OPCs and decreased numbers of oligodendrocytes in the spinal cord [27; 107]. In contrast, loss of Nkx2.2 results in increased numbers of OPCs [28]. Strong Olig2 or Nkx2.2 signals were observed in OPCs in the spinal cord of adult mice, while mature oligodendrocytes expressed low levels of these two transcription factors suggesting that a specific pattern of transcription factor coexpression correlates with the stage of OPC/oligodendrocyte maturation [26]. As transcription factors and the myelin genes they induce are the final targets of many of the molecules discussed in this review, direct targeting of myelin gene expression as a method to treat remyelination failure in MS may prove to be the most powerful approach.

Concluding Remarks

Although studies demonstrate that the CNS is capable of responding to myelin damage by triggering developmental mechanisms that induce remyelination, it is unclear why endogenous repair mechanisms ultimately fail in patients with MS. Given that OPCs and premyelinating oligodendrocytes may be detected in acute MS lesions [108], it would seem that remyelination is likely hindered by a block in differentiation pathways. Molecules that interfere with remyelination may be derived from infiltrating immune cells or activated glia, as discussed above [18; 109]. Of interest, chronically demyelinated lesions are frequently observed to contain few OPCs and mostly activated astrocytes [108; 110], suggesting that astrogliosis prevents OPC differentiation or that OPCs that fail to differentiate along the oligodendrocyte lineage induce astrogliosis or, somehow, become astrocytes themselves [111]. It is also possible that the repair mechanisms triggered by CNS damage during MS not only contribute to chronic leukocyte infiltration but also induce neuronal injury responses that prevent remyelination. Future studies will ultimately identify these context-specific molecules that impact on neural precursor cell differentiation.

Figure 1. Putative Remyelination Mechanisms.

Depicted are roles for cytokines, chemokines, growth factors, transcription factors and other signaling proteins in remyelination of demyelinated lesions in MS. During demyelination, oligodendrocytes undergo apopotosis, leaving debris, which may contribute to the activation of microglia and astrocytes, which then express cytokines (TNF-α, IL-1β) [15–16]. Cytokines alter expression of chemokines (CXCL1, CXCL2, CXCL12) and growth factors (IGF-1, PDGF, FGF, EGF), whose activation or inhibition of various aspects of remyelination are depicted via color-coding of arrows and signs of blockade, respectively, for each biologic process (migration, proliferation, OPC survival and differentiation). For certain molecules, such as CXCL1/2, opposing effects on OPCs have been observed, depending on the animal model used. Growth factors differentially impact on cell survival and proliferation while chemokines contribute to migration and differentiation, depending on OPC position. TLR2 activation inhibits OPC differentiation [79]. Notch-1 also blocks OPC differentiation to promote migration. Molecules that regulate OPC maturation are depicted in the context of intracellular signaling during differentiation. Included are chemokine (CXCR4/7, CXCR2) and growth factor (IGF-1R, EGFR) receptors, miRNAs, Lingo-1 and several transcription factors (Nkx2.2, Olig1/2, Mash1, Tcf4, SOX10) which may negatively or positively impact on the expression of myelin proteins including proteolipid protein (PLP), myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG).

Abbreviations

CNS

central nervous system

CNPase

2′, 3′-cyclic nucleotide 3′-phosphodiesterase

EAE

experimental autoimmune encephalomyelitis

EC

endothelial cells

EGF

epidermal growth factor

FGF

fibroblast growth factor

IL-1β

Interleukin-1 beta

OPC

oligodendrocyte precursor cell

PDGF

platelet-derived growth factor

PLP

proteolipid protein

MBP

myelin basic protein

MHV

mouse hepatitis virus

MS

multiple sclerosis

MOG

myelin oligodendrocyte glycoprotein

SVZ

subventricular zone

TNFα

tumor necrosis factor alpha

TLR

Toll-like receptors