You are here
Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis
Neuropharmacology, In Press, Corrected Proof, Available online 22 October 2015, Available online 22 October 2015
Oligodendrocytes readily regenerate and replace myelin membranes around axons in the adult mammalian central nervous system (CNS) following injury. The ability to regenerate oligodendrocytes depends on the availability of neural progenitors called oligodendrocyte precursor cells (OPCs) in the adult CNS that respond to injury-associated signals to induce OPC expansion followed by oligodendrocyte differentiation, axonal contact and myelin regeneration (remyelination). Remyelination ensures the maintenance of axonal conduction, and the oligodendrocytes themselves provide metabolic factors that are necessary to maintain neuronal integrity. Recent advances in oligodendrocyte regeneration research are beginning to shed light on critical intrinsic signals, as well as extrinsic, environmental factors that regulate the distinct steps of oligodendrocyte lineage progression and myelin replacement under CNS injury. These studies may offer novel pharmacological targets for regenerative medicine in inflammatory demyelinating disorders in the CNS such as multiple sclerosis.
- Oligodendrocytes regenerate and remyelinate axons following injury.
- Remyelination is important in maintaining axonal conduction and integrity.
- Pharmacological targeting of remyelination may improve repair in multiple sclerosis.
Keywords: Oligodendrocytes, Regeneration, Myelin, Remyelination, Inflammation, Multiple sclerosis, Oligodendrocyte precursor cells.
Oligodendrocytes are glial cells that extend myelin membranes around axons in the central nervous system (CNS). In between myelin segments are unmyelinated axonal regions termed nodes of Ranvier, where sodium channels involved in action potential generation are clustered. This exquisite organization defines the typical vertebrate nerve fiber and is crucial for saltatory propagation of electrical impulses down the axon, enabling rapid communication between networks of nerve cells in the CNS (Bhatt et al, 2014, Frankenhaeuser, 1952, and Hartline and Colman, 2007). In addition to increasing axonal conduction speed through generating myelin, oligodendrocytes secrete metabolic factors that maintain the integrity and survival of CNS neurons (Edgar et al, 2009, Fünfschilling et al, 2012, Griffiths et al, 1998, Lee et al, 2012, and Oluich et al, 2012). Disturbances to oligodendrocyte function or myelination in the developing or injured brain impairs axonal conduction (Waxman, 2006) and is associated with neuronal degeneration (Haines et al., 2009), highlighting the importance of oligodendrocytes in maintaining CNS function.
One of the most intriguing features of the adult CNS is its ability to spontaneously regenerate oligodendrocytes and replace myelin (remyelination) following acute demyelination (Franklin and Ffrench-Constant, 2008). Oligodendrocyte regeneration is possible because of an abundantly distributed source of oligodendrocyte precursor cells (OPCs) in the adult CNS (Dawson et al, 2003, Horner et al, 2002, Pringle et al, 1992, and Van Wijngaarden and Franklin, 2013). Following demyelination, neighboring OPCs rapidly migrate to the site of injury where they differentiate into oligodendrocytes to remyelinate recently denuded axons. This spontaneous regenerative response restores saltatory conduction (Smith et al., 1979) and has been suggested to protect axons from degeneration (Irvine and Blakemore, 2008, Jeffery and Blakemore, 1997, and Kornek et al, 2000). Failure to regenerate oligodendrocytes and replace myelin exacerbates axonal dysfunction from myelin loss, leading to a cascade of pathological events that ultimately concludes with neurodegeneration (Trapp and Stys, 2009). Clinical manifestations of acute CNS demyelination followed by spontaneous remyelination, as well as the progressive neurodegeneration associated with remyelination failure, are most evident in the chronically demyelinating disorder, multiple sclerosis (MS).
MS is an immune-mediated neurological disease affecting more than 2.3 million people worldwide (Milo and Kahana, 2010; Compston and Coles, 2008). For reasons that remain poorly understood, myelin membranes and oligodendrocytes are destroyed through chronic inflammation in the CNS. Although efficient oligodendrocyte regeneration and remyelination occurs in the early stages of MS, remyelination becomes inefficient and ultimately fails with disease progression (Franklin and ffrench-Constant, 2008). The mechanism of remyelination failure remains unclear, however it has been hypothesized that OPCs become “stalled” and may fail to differentiate into mature oligodendrocytes at sites of lesions (for review see Franklin, 2002). Since remyelination restores axonal conduction and protects against axonal damage in rodent models of MS (Irvine and Blakemore, 2008, Jeffery and Blakemore, 1997, and Kornek et al, 2000), it is hypothesized that pro-remyelination therapies may be beneficial for patients with MS. In order to understand the biology of remyelination and to develop therapies to enhance this process in MS, several models of experimental demyelination are used. We have provided an abbreviated description of the most widely used model systems in Table 1. More thorough reviews have been published elsewhere (Blakemore and Franklin, 2008, Pachner, 2011, Rodriguez, 2007, and Tanaka and Yoshida, 2014). In this review we discuss the neuroprotective functions of oligodendrocytes, molecular pathways involved in regulating their regeneration, and possible therapeutic targets for promoting remyelination in the CNS.
|Model||Mechanism||Aspect(s) of MS modeled||Pros||Cons|
|Autoimmune experimental autoimmune/allergic encephalomy-elitis (EAE)||Co-injection of pertussis toxin and a specific myelin protein (MOG,MBP, or PLP) causes myelin destruction mediated primarily by invasion of peripheral antigen-specific T cells.||
|Theiler's murine encephalomyelitis virus (TMEV)||Intracerebral infection with TMEV in susceptible mouse strains leads to chronic demyelination primarily in the spinal cord.||
|Toxin induced models:|
|Lysolecithin||Focal injection of 1% lysolecithin, an activator of phospholipase A2, into the spinal cord produces local demyelination.||
|Cuprizone||Administration of 0.2% cuprizone, a copper chelator, in the chow leads to mitochondrial complex IV dysfunction and oligodendrocyte toxicity, leading to demyelination in the corpus callosum and hippocampus.||
a (Denic et al., 2011).
b (Baxter, 2007).
c (Ransohoff, 2012).
2. Role of oligodendrocytes in myelination and neuroprotection
Oligodendrocytes extend myelin sheaths around axons in a stereotyped fashion, leaving intermittent gaps of unmyelinated axon, termed nodes of Ranvier, between adjacent myelinated segments or internodes. This precise organization enables the restriction of voltage gated sodium channels to nodes of Ranvier and voltage gated potassium channels to areas called juxtaparanodes (Pedraza et al, 2001, Rasband, 2010, and Rasband, 2008). Demyelination disrupts ion channel segregation (Coman et al, 2006 and Wolswijk and Balesar, 2003), such that sodium and potassium channels redistribute along the axon, causing overlap of paranodal and juxtaparanodal protein domains (Craner et al, 2004, England et al, 1990, Podbielska et al, 2013, and Scherer and Arroyo, 2002). The diffusion of ion channels and increased membrane capacitance from myelin loss produce an impedance mismatch in demyelinated axons, which causes inefficient conduction (Waxman, 2006). In MS, the manifestation of impaired impulse conduction is frequently associated with functional and/or cognitive disabilities, highlighting the importance of intact myelin around CNS axons for mediating efficient communication between neural networks (Charil et al., 2003).
In addition to their role in myelination, recent studies have found that oligodendrocytes play a critical role in maintaining axonal integrity (Edgar et al, 2009, Griffiths et al, 1998, Lappe-Siefke et al, 2003, Nave and Trapp, 2008, Nave, 2010, and Saab et al, 2013). For example, mice deficient in proteolipid protein (PLP1) or CNP, major oligodendrocyte proteins found in myelin, do not display obvious structural abnormalities in myelin, but display impaired axonal transport (Edgar et al, 2010 and Edgar et al, 2009). Moreover, targeted ablation of oligodendrocytes in mice resulted in axonal pathology (Oluich et al, 2012 and Traka et al, 2010). Exactly how oligodendrocytes maintain axonal integrity remains unclear. Several studies have observed that mitochondrial density in axons increases significantly in demyelinated lesions in MS and after experimental demyelination in mice, suggesting that the presence of myelin or oligodendrocytes may be important in regulating axonal energy metabolism (Campbell et al, 2012, Kiryu-Seo et al, 2010, Mutsaers and Carroll, 1998, Traka et al, 2010, and Zambonin et al, 2011). It is possible that oligodendrocytes provide metabolic factors to the axon in order to meet its high energetic demand, and that the absence of oligodendrocyte support may render neurons vulnerable to oxidative damage and cell death (Nave, 2010). Indeed, recent studies have found that lactate transport to neurons is crucial for maintaining neuronal health and survival (Fünfschilling et al, 2012 and Lee et al, 2012). The downregulation of the lactate transporter MCT1 in oligodendrocytes has recently been shown to result in impaired lactate transport, leading to neuronal dysfunction and degeneration (Lee et al., 2012).
In addition to supporting axonal energy metabolism, oligodendrocytes may also regulate neuronal survival through the production of neurotrophic factors. Several previous studies have suggested that oligodendrocytes express brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) mRNA (Byravan et al, 1994, Dai et al, 2003, Dougherty et al, 2000, Gonzalez et al, 1990, and Zhang et al, 2014). Moreover, BDNF and NT-3 secretion from oligodendrocytes have been shown to enhance the function of basal forebrain neurons in vitro, by increasing the expression choline acetyltransferase (ChAT) (Dai et al., 2003). Moreover, oligodendrocytes may also express glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor type-1 (IGF1), and both factors have been shown to enhance cortical neuron survival (Wilkins et al., 2001, 2003; Zhang et al, 2014 and Wilkins and Compston, 2005). However, most of these studies were performed in vitro, so further studies are needed to understand the role of neurotrophic factors and IGF1 in oligodendrocyte-mediated neuronal survival in vivo.
3. Drivers of disease progression: axon damage and neurodegeneration
Considering the many roles of oligodendrocytes in supporting neuronal health, it may not be surprising that remyelination failure in progressive MS is accompanied by neurodegeneration (Compston and Coles, 2008, Dutta and Trapp, 2011, Haines et al, 2009, and Nave and Trapp, 2008). It is hypothesized that the degeneration of axons in the chronically demyelinated CNS is a cause of irreversible disability (Mahad et al, 2015 and Wegner et al, 2006). The evidence for axonal damage in MS is robust and comes from clinical, histopathological, biochemical, and imaging studies (for review see Haines et al, 2011 and Trapp and Nave, 2008). Notably, although current immunosuppressive therapies reduce the number of relapses, they do not prevent patients from progressing (Carrithers, 2014 and Rice, 2014) or developing significant cortical atrophy (Sailer et al., 2003). In fact, early in the disease, brain atrophy positively correlates with subsequent disability progression (Fisher et al, 2002 and Rudick et al, 1999). MS patients with permanent paralysis are estimated to have between 60 and 70% axonal loss (Bjartmar et al, 2000 and Mews et al, 1998) and this finding is closely recapitulated in the chronic EAE model, in which mice with permanent paralysis exhibit 59% and 43% axonal loss in the cervical and lumbar spinal cord, respectively (Wujek et al., 2002). Histologically, acute axon damage is characterized by the presence of varicosities and spheroid structures (Saxena and Caroni, 2007), which reflect impaired organelle transport in the axon (Williamson and Cleveland, 1999). This impairment results in the accumulation of proteins, including amyloid precursor protein (APP), along the damaged axon. APP accumulation is present in active, remyelinating, and inactive MS lesions (Bitsch et al, 2000 and Ferguson et al, 1997). A second marker of neurodegeneration, non-phosphorylated neurofilament heavy chain (NFH), also accumulates in neurons in MS lesions (Dziedzic et al, 2010, Gray et al, 2012, Petzold et al, 2008, and Schirmer et al, 2011).
Axon damage occurs in both acute demyelinating lesions and in chronically demyelinated lesions (Ciccarelli et al, 2014, Ferguson et al, 1997, and Trapp et al, 1998), however it remains unknown whether this is a consequence of direct inflammatory attack, secreted inflammatory mediators, or is a secondary effect of demyelination (Haines et al, 2011 and Trapp et al, 1998). Observations of neuronal loss and dendritic atrophy in normal appearing white matter (NAWM) (Bjartmar et al, 2000, Trapp et al, 1998, and Wood et al, 2012), and in normal appearing gray matter (NAGM) (Klaver et al., 2015) suggest an early pathogenic mechanism. A growing body of evidence suggests that energetic failure and oxidative stress may be a driving factor of neurodegeneration (Trapp and Stys, 2009), as abnormalities in mitochondria density, morphology, and activity are consistently found in models of MS (Campbell et al, 2014, Fischer et al, 2012, Joshi et al, 2015, Kiryu-Seo et al, 2010, Mahad et al, 2008, Mahad et al, 2009, Qi et al, 2006, Witte et al, 2014, Witte et al, 2010, and Witte et al, 2009). The exact cause of neurodegeneration in MS remains to be seen, however the demonstration that early axonal damage can be reversed with remyelination (Bjartmar et al, 2003 and Nikić et al, 2011) strengthens the rationale that pro-remyelination therapies could be beneficial for the treatment of MS.
4. Restoring function: mediators of oligodendrocyte regeneration and remyelination
Remyelination is remarkably prolific in the early stages of MS (Franklin, 2002, Goldschmidt et al, 2009, and Patrikios et al, 2006), but becomes less efficient with disease progression for unknown reasons (Goldschmidt et al, 2009 and Franklin, 2002). While OPCs continue to be recruited to demyelinated regions in approximately 70% of lesions (Chang et al, 2002 and Lucchinetti et al, 1999), their differentiation into re-myelinating cells is halted (Back et al, 2005, Charles et al, 2002, Charles et al, 2000, Fancy et al, 2010, and Mi et al, 2005). Thus, it was hypothesized that impairment of OPC differentiation contributes to remyelination failure (Chang et al, 2002, Huang and Franklin, 2011, Kuhlmann et al, 2008, and Wolswijk, 1998). Here, we will describe the role of intrinsic signaling pathways known to regulate OPC differentiation and how this process is influenced by extrinsic signals from the surrounding inflammatory milieu (Fig. 1).
4.1. Intrinsic mediators of OPC differentiation
Several molecular pathways have been implicated in the inhibition of OPC differentiation. It is likely that transcriptional repression of these inhibitory pathways, combined with transcriptional activation of myelin genes, regulates OPC differentiation (Li et al., 2009). Here, we discuss the most widely studied inhibitory pathways including LINGO-1, canonical Notch, canonical wingless (Wnt), and semaphorin signaling. In addition, we discuss the few signaling cascades known to stimulate endogenous oligodendrocyte regeneration, including RXR and muscarinic receptor signaling pathways.
4.1.1. LINGO-1 signaling
LINGO-1 (leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1), a membrane protein expressed in neurons and oligodendrocytes, negatively regulates oligodendrocyte differentiation in rodent (Ji et al, 2006, Lee et al, 2007, and Mi et al, 2005) and zebrafish (Yin and Hu, 2014). LINGO-1 knockout mice exhibit enhanced myelin sheath formation and recovery from EAE (Mi et al, 2007 and Mi et al, 2005). Similarly, treatment with a LINGO-1 antagonist results in increased OPC differentiation and enhanced remyelination following EAE and lysolecithin-mediated demyelination (Mi et al., 2009), suggesting that LINGO-1 inhibition may be a useful therapeutic approach. Indeed, anti-LINGO-1 antibody promotes remyelination following lysolecithin-mediated demyelination (Zhang et al., 2015) and excitingly, has proven safe and well tolerated in patients (Tran et al., 2014). Now in a Phase II randomized clinical trial, LINGO-1 antibody may become the first available MS drug for promoting remyelination (Rudick et al., 2008). Precisely how LINGO-1 exerts its pro-regenerative effect in models of MS remains to be seen. A recent study demonstrated that LINGO-1 inhibition of oligodendrocyte differentiation may be due to decreased lipid raft translocation of the tyrosine kinase receptor ErbB2 (Lee et al., 2014). The ErbB receptor family, which also includes epidermal growth factor receptor (EGFR) and the neuregulin receptors, ErbB3 and ErbB4, has been implicated in the modulation of oligodendrocyte differentiation and myelination, albeit in a convoluted manner. ErbB2 deficiency halts oligodendrocyte lineage cells in an early stage leading to reductions in terminally differentiated oligodendrocytes (Kim et al, 2003 and Park et al, 2001). While ErbB3 and ErbB4 are not required for oligodendrocyte differentiation (Brinkmann et al, 2008, Stolt et al, 2002, and Sussman et al, 2005), ErbB3 may mediate experience-dependent myelination (Makinodan et al., 2012). At this point, it remains unclear whether targeting ErbB receptors would improve outcome in models of MS. Results from the anti-LINGO-1 clinical trial should inform the future direction of research in this area.
4.1.2. Canonical notch signaling
The Notch receptors are a family of transmembrane proteins that are cleaved when activated to modulate gene expression (Brosnan and John, 2009 and D'Souza et al, 2008). It is generally established that canonical Notch signaling, which occurs through ligands such as Jagged, inhibits OPC differentiation during development. Activation of Notch1 receptors on OPCs inhibits their differentiation in vitro (Wang et al., 1998) and inhibition of Notch1 in OPCs disrupts the spatial and temporal regulation of oligodendrocyte differentiation in the spinal cord (Genoud et al., 2002). Further, mice heterozygous for the null allele of Notch1 exhibit premature oligodendrocyte differentiation and increased myelination (Givogri et al., 2002). Genetic inactivation of Notch1 in OPCs produces a similar phenotype characterized by premature OPC differentiation (Zhang et al., 2009). Although these studies suggest that Notch1 controls the time-course of OPC differentiation during development, its role in CNS remyelination appears more convoluted. Mice undergo complete spontaneous remyelination (Stidworthy et al., 2004) despite re-expression of Notch1 and Jagged1 in demyelinated lesions (John et al, 2002, Seifert et al, 2007, and Stidworthy et al, 2004), bringing into question the role of this signaling pathway in remyelination. Genetic inactivation of Notch1 in OPCs has yielded conflicting results (Stidworthy et al, 2004 and Zhang et al, 2009), however Hammond et al. recently demonstrated that OPC differentiation following lysolecithin demyelination is inhibited by Jagged1-expressing astrocytes, which directly bind to Notch1 on OPCs (Hammond et al., 2014). Reactive astrocytes express Jagged1 in MS plaques (John et al., 2002) and this expression appears to be regulated by the secreted protein endothelin-1 (ET-1) (Hammond et al., 2014), which is upregulated following lysolecithin-mediated demyelination (Gadea et al., 2008) and inhibits oligodendrocyte differentiation during development (Gadea et al., 2009). Although ET-1 directly inhibits OPC differentiation and migration in vitro (Gadea et al., 2009), it is the indirect regulation of Jagged1 expression on reactive astrocytes that is proposed to inhibit OPC differentiation following demyelination (Hammond et al., 2014). ET-2 is also implicated in the regulation of CNS remyelination, as it has been shown to promote OPC differentiation and remyelination in a model of innate immunity (Yuen et al., 2013). However, a link between ET-2 and Notch signaling has not been identified to our knowledge. Although more work is needed to identify the precise function of Notch signaling in mediating the progression of oligodendrocyte lineage cells, the majority of findings implicate this pathway in the inhibition of OPC differentiation.
4.1.3. Wnt signaling
Wnt proteins are secreted ligands that play numerous roles in regulating development, including oligodendrocyte genesis (Azim and Butt, 2011, Fancy et al, 2009, Ortega et al, 2013, Shimizu et al, 2005, and Ye et al, 2009). The canonical Wnt pathway is activated when extracellular Wnt binds to Frizzled membrane receptors, resulting in the stabilization of intracellular β-catenin, which enters the nucleus to promote Wnt gene transcription (Xie et al., 2014). Shimizu et al. (2005) showed that OPC differentiation in the spinal cord is inhibited by Wnt signaling through the canonical β-catenin pathway (Shimizu et al., 2005). Similarly, upregulating Wnt signaling decreases the number of proteolipid protein (PLP)-positive oligodendrocytes (Azim and Butt, 2011 and Fancy et al, 2009). Interestingly, a recent study demonstrated that clustering of Frizzled receptors and the subsequent transduction of Wnt signals is modulated by Daam2-PIP5K (Lee et al., 2015). Daam2 may be a potential upstream target of Wnt as its activation inhibits OPC differentiation in development and white matter injury (WMI) (Lee et al., 2015). Although there is a general consensus that canonical Wnt signaling inhibits OPC differentiation, conflicting findings have been reported (Xie et al., 2014). Wnt/β-catenin signaling pathway is essential for myelin protein expression and myelin sheath compaction in zebrafish (Tawk et al., 2011). In addition, decreased MBP and PLP are found in mice lacking T-cell factor 4 (Fu et al., 2009), a transcription factor downstream of β-catenin that is expressed by OPCs during development and remyelination (Fancy et al., 2009). These studies suggest that Wnt/β-catenin signaling serves distinct functions in oligodendrocyte specification, differentiation, and myelination depending on timing and dosage (Xie et al., 2014). In support of this hypothesis, Wnt pathway activation was found to affect oligodendrocyte lineage cells in a dose-dependent fashion; low Wnt tone allows OPCs to differentiate and high Wnt tone after injury is associated with permanent WMI (Fancy et al., 2014). Importantly, most studies demonstrate an inhibitory role for Wnt signaling in remyelination. Mice lacking one copy of APC, a β-catenin antagonist, exhibit severely diminished PLP + oligodendrocytes and remyelination (Fancy et al, 2009 and Lang et al, 2013). Moreover, mice lacking Axin2, a Wnt target gene that promotes the degradation of β-catenin (Behrens et al, 1998 and Jho et al, 2002), exhibit impaired OPC differentiation and delayed remyelination (Fancy et al., 2011b). Axin2 is expressed in OPCs in active MS lesions and in human hypoxic-ischemic white matter lesions (Fancy et al., 2011b), suggesting it may be a viable therapeutic target. More work is needed to elucidate the mechanisms by which Wnt signaling regulates oligodendrocyte lineage cells embryonically, postnatally, and following injury (Azim et al, 2014, Dai et al, 2014, and Rodriguez et al, 2014) in order to resolve the ongoing debate about how and when to modulate Wnt signaling to effectively stimulate remyelination (Guo et al., 2015). Several Wnt inhibitory compounds have been identified as potential anti-cancer therapies (Le et al., 2014). Thus, inhibiting Wnt pathways as a pro-remyelination strategy may be feasible in the near future (Fancy et al, 2011a and Huang and Franklin, 2011).
4.1.4. Semaphorin signaling
Failure of OPCs to migrate into demyelinated lesions may contribute to failed remyelination in approximately 30% of MS lesions which exhibit reduced OPC numbers (Chang et al, 2002 and Lucchinetti et al, 1999). Semaphorins are a family of secreted and membrane proteins that have been implicated in this context. Semaphorins regulate neural development primarily by forming migratory cues through extracellular matrix binding to plexin and neuropillin receptors (for review see Jongbloets and Pasterkamp, 2014). Several members of the semaphorin family have been implicated in regulating OPC migration and differentiation, including semaphorin 3A (SEMA3A), 3F (SEMA3F), and 4D (SEMA4D). Interestingly, SEMA3A and SEMA3F play opposing roles in regulating OPC migration during development. SEMA3A serves as an inhibitory migratory cue whereas SEMA3F serves as an attractive migratory cue (Spassky et al, 2002 and Sugimoto et al, 2001). While these proteins are down-regulated in the adult, SEMA3A and SEMA3F are re-expressed in active demyelinating lesions (Williams et al., 2007) where they inhibit and promote OPC migration, respectively (Piaton et al., 2011). Knockdown of SEMA3A promotes in vivo remyelination following focal demyelination of corpus callosum (Boyd et al., 2013). This effect was due to increased OPC migration into the lesion, whereas OPC proliferation, differentiation, and apoptosis were unaffected (Boyd et al., 2013). In contrast, another study found that SEMA3A directly inhibits OPC differentiation in vitro (Syed et al., 2011). While this discrepancy may be explained by different doses of SEMA3A or the use of different species, both groups show that the downstream effect of SEMA3A signaling is failed remyelination (Boyd et al, 2013 and Syed et al, 2011). SEMA4D is also inhibitory, as it induces collapse of oligodendrocyte cell processes (Giraudon et al., 2004) and inhibits both OPC survival and differentiation (Smith et al., 2015). Blocking SEMA4D with a monoclonal antibody promotes OPC migration to lesions and improves myelin status following focal demyelination (Smith et al., 2015). Because diminished OPC migration likely contributes to failed remyelination in some MS lesions (Chang et al, 2002 and Lucchinetti et al, 1999), inhibiting SEMA4D could be beneficial for MS. While these studies suggest that targeting semaphorins may be beneficial for promoting remyelination, further validation and human trials are needed to thoroughly assess the efficacy of this approach.
4.1.5. RXR signaling
To date, only a few signaling cascades have been identified for stimulating oligodendrocyte regeneration. Among them is the nuclear retinoid X receptor (RXR) pathway, which plays an important role in cell proliferation and development (for review see Mark et al., 2009). RXRs couple with several other nuclear receptors including retinoic acid receptor, vitamin D receptor, thyroid receptor, and peroxisome proliferator-activated receptor to induce gene transcription (Rastinejad, 2001). The RXR-γ isoform is the first identified nuclear receptor to play a role in promoting remyelination. Huang et al. (2011) found that RXR-γ is differentially upregulated during remyelination in rodent and in active and remyelinated MS lesions (Huang et al., 2011). Further, knockdown of RXR-γ receptor by RNA interference/RXR-specific antagonists dramatically reduces OPC differentiation in vitro and RXR-γ knockout mice exhibit significantly less mature oligodendrocytes following demyelination (Huang et al., 2011). These studies suggest that RXR-γ signaling may regulate oligodendrocyte differentiation and open new doors for pharmacological targeting using RXR ligands, many of which are under study or already approved for the treatment of certain cancers (Ballanger et al., 2010).
4.1.6. Muscarinic signaling
Acetylcholine muscarinic receptors (mAChR) have been widely studied as potential drug targets for Alzheimer's disease, Parkinson's disease, and schizophrenia (Langmead et al., 2008). A recent study using high-throughput screening for MBP expression in primary rat progenitor cells identified Benztropine, a selective M1 mAChR antagonist used for treating Parkinson's Disease, as an enhancer of OPC differentiation in vitro (Deshmukh et al., 2013). Benztropine also promoted OPC differentiation in the EAE and cuprizone models of demyelination (Deshmukh et al., 2013). The beneficial effect of Benztropine is thought to result from direct anticholingeric activity on OPCs (Deshmukh et al, 2013 and Eshleman et al, 1994). However, because Benztropine also has anti-histaminic activity (McKearney, 1982) and can inhibit dopamine uptake (Agoston et al., 1997), more work is needed to confirm the mechanism of action. Further, although Benztropine is still used in the clinical treatment of Parkinson's disease (Katzenschlager et al., 2003), it is associated with severe side effects such as impaired cognition, urinary retention, nausea, and constipation (Lang and Lees, 2002 and Lees, 2005). Recently, Mei et al. (2014) discovered a cluster of eight FDA-approved antimuscarinic compounds that enhance OPC differentiation and myelination using a novel micropillar assay for high-throughput screening. One drug in particular, Clemastine, readily passes the BBB and was highly effective in promoting OPC differentiation and myelination in their assay (Mei et al., 2014). Although more in vivo validation is needed, muscarinic receptors seem to be an exciting new target for the development of MS therapeutics.
4.2. Influence of extrinsic inflammatory cues on OPC differentiation
Both microglia, the resident immune cells of the CNS, and peripherally derived macrophages play critical roles in neuroinflammatory disorders. Although they have different developmental origin and localization under physiological conditions, both macrophages and microglia can be polarized to acquire distinct phenotypes and functions (Colton, 2009). We will discuss the generalized activation states of macrophages/microglia as classically-activated macrophages/microglia (CAM) and alternatively-activated macrophages/microglia (AAM) because these are the most widely studied in the context of neuroinflammatory disorders. It is important to note that the distinction between CAM and AAM is not always clear, as microglia and macrophages are plastic and respond rapidly to changes in their environment and can acquire a diverse range of activation programs depending on the stimuli received (Katsumoto et al., 2014).
CAM are the first to respond to an injury or infection by secreting pro-inflammatory cytokines, reactive oxygen species (ROS), and nitrogen species to create an unfavorable (inflammatory) environment for the survival of pathogens (Mantovani et al., 2013). Additionally, CAM have an increased capacity for antigen-presentation. In the context of MS, this leads to widespread primary demyelination by promoting the phagocytosis of myelin fragments and dying oligodendrocytes by macrophages/microglia and reactive astrocytes (Lassmann, 2014, Sosa et al, 2013, and Wu and Raine, 1992). Conversely, AAM are generally thought to suppress inflammation by promoting debris removal, angiogenesis, tissue remodeling, and wound healing (Mantovani et al., 2013).
Although inflammation leads to oligodendrocyte death and demyelination, depletion of immune cells including macrophages, microglia, and T cells or removal of pro-inflammatory factors including TNFα, IL-1β, and MHCII paradoxically impairs the remyelination process (Arnett et al, 2001, Bieber et al, 2003, Kotter et al, 2005, and Mason et al, 2001). Interestingly, remyelination of aged mice, which exhibit impaired OPC recruitment and differentiation (Sim et al., 2002), is enhanced when blood circulation is shared with young mice via parabiosis (Miron et al, 2013 and Ruckh et al, 2012). Shared circulation stimulated differentiation and remyelination of endogenous, aged OPCs in old animals following demyelination, an effect that may be partially mediated by the recruitment of young macrophages (Kotter et al, 2006, Miron et al, 2013, Ruckh et al, 2012, and Shechter and Schwartz, 2013). More work is needed to elucidate the contribution of potentially additive cell types or other circulating factors to the pro-regenerative effect of young/old parabiosis, however these experiments strongly suggest that the inflammatory environment can be modulated to promote remyelination.
Activated macrophages/microglia might promote remyelination by phagocytosing myelin debris, which is known to inhibit regeneration (Copelman et al, 2001, Ousman and David, 2000, and Robinson and Miller, 1999), or by secreting pro-remyelination cytokines and growth factors (Arnett et al, 2001, Hinks and Franklin, 1999, Kotter et al, 2005, Mason et al, 2001, and Vela et al, 2002). AAM seem to be particularly important for the beneficial effect of inflammation on remyelination as their depletion leads to delayed oligodendrocyte differentiation following demyelination (Miron et al., 2013). Further, increasing the number of AAM attenuates symptoms in EAE mice (Denney et al, 2012 and Mikita et al, 2011). The paradoxical effects of inflammation in MS suggest that it may be the balance of CAM and AAM that sets the tone for remyelination. In support of this hypothesis, Mikita et al. (2011) found that while CAM and AAM are relatively balanced after the first clinical attack following EAE induction, the CAM population significantly outnumbers the AAM population during relapse (Mikita et al., 2011). This work suggests that therapeutically manipulating the balance of CAM/AAM may be beneficial for promoting remyelination in chronic lesions. Significantly more work is needed to elucidate how CAM/AAM balance is regulated and how this balance changes with disease progression in order to test this hypothesis.
4.2.1. Contribution of reactive astrocytes
Astrocytes, the most abundant cells in the CNS, play numerous roles in the healthy brain as well as in disease (Mayo et al., 2014). In a process known as astrogliosis, they rapidly respond to injury by becoming “activated,” a phenotype characterized by altered protein expression, cell morphology remodeling, and the upregulation of proinflammatory cytokines (eg. IL6, iNOS, TNFalpha) and growth factors (eg. LIF, IGF1, PDGFalpha, CNTF) (Sofroniew, 2009). Reactive astrocytes are also characterized by increased proliferation, cellular hypertrophy, and process extension, which are thought to contribute to glial scar formation. While glial scar formation restricts infection and cell necrosis to avoid damaging adjacent tissue (Sofroniew, 2009), it can also be detrimental by contributing to chronic inflammation and blockage of oligodendrocyte lineage cell migration into the lesion (Bannerman et al, 2007 and Mayo et al, 2014).
Reactive astrocytes appear to have direct and indirect effects on oligodendrocyte lineage cells. For example, expression of Jagged1 receptors on astrocytes directly inhibits OPC differentiation via Notch signaling (Hammond et al, 2014, Stidworthy et al, 2004, and Zhang et al, 2009) as described in section 4a. Activated astrocytes play additional, indirect roles in regulating OPC differentiation by affecting macrophages/microglia and infiltrating T-cells. Mice lacking astrocytic NF-kB, a transcription factor that alters production of pro-inflammatory cytokines, have reduced infiltration of inflammatory cells in the spinal cord and less cytokine secretion by T cells following EAE induction (Brambilla et al, 2014 and Brambilla et al, 2009). Similarly, the astrocyte-derived enzyme B4GALT6 (β-1,4-galactosyltransferase 6), has recently been identified as a driver of neuroinflammation and of microglia/macrophage activation and recruitment in chronic EAE (Mayo et al., 2014). Reactive astrocytes also indirectly affect OPC differentiation by contributing to increased BBB permeability via secretion of thymidine phosphorylase (TYMP) and vascular endothelial growth factor A (VEGF-A) (Argaw et al, 2012 and Chapouly et al, 2015). Deletion of VEGF-A specifically in astrocytes improves outcome in the lysolecithin and EAE models of MS, likely by reducing the infiltration of monocytes into the CNS (Argaw et al., 2012). While it is clear that astrocytes contribute to the pathology of MS, future work should focus on identifying the mechanisms by which astrocytic signals directly affect OPC differentiation as well as regulate the inflammatory environment.
In lieu of a cure, oligodendrocyte regeneration may be a useful therapeutic approach for the treatment of MS. Remyelination restores the physiological interaction between oligodendrocyte and axon, and is hypothesized to restore the necessary structural and secreted support for axonal maintenance and efficient impulse conduction. Here we discussed several molecular pathways that regulate differentiation of OPCs into mature, myelinating oligodendrocytes that should be carefully considered as possible therapeutic targets. In conjunction, the state of inflammation must be carefully weighed. As it is now appreciated that inflammation is both damaging to myelin and necessary for myelin regeneration, combination therapies may be needed to promote remyelination across a changing inflammatory background.
- Agoston et al., 1997 G. Agoston, J. Wu, S. Izenwasser, C. George, J. Katz, R. Kline, A. Newman. Novel N-substituted 3r-[Bis(4′-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. J. Med. Chem.. 1997;40:4329-4339
- Argaw et al., 2012 A.T. Argaw, L. Asp, J. Zhang, K. Navrazhina, T. Pham, J.N. Mariani, S. Mahase, D.J. Dutta, J. Seto, E.G. Kramer, N. Ferrara, M.V. Sofroniew, G.R. John. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest.. 2012;122:2454-2468 10.1172/JCI60842
- Arnett et al., 2001 H. Arnett, J. Mason, M. Marino, K. Suzuki, G.K. Matsushima, J.P. Ting. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci.. 2001;4:1116-1122 10.1038/nn738
- Azim and Butt, 2011 K. Azim, A.M. Butt. GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo. Glia. 2011;59:540-553 10.1002/glia.21122
- Azim et al., 2014 K. Azim, A. Rivera, O. Raineteau, A.M. Butt. GSK3β regulates oligodendrogenesis in the dorsal microdomain of the subventricular zone via Wnt-β-catenin signaling. Glia. 2014;62:778-789 10.1002/glia.22641
- Back et al., 2005 S.A. Back, T.M.F. Tuohy, H. Chen, N. Wallingford, A. Craig, J. Struve, N.L. Luo, F. Banine, Y. Liu, A. Chang, B.D. Trapp, B.F. Bebo, M.S. Rao, L.S. Sherman. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat. Med.. 2005;11:966-972 10.1038/nm1279
- Ballanger et al., 2010 F. Ballanger, J.M. Nguyen, a. Khammari, B. Dréno. Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma. Dermatology. 2010;220:370-375 10.1159/000305354
- Bannerman et al., 2007 P. Bannerman, A. Hahn, A. Soulika, V. Gallo, D. Pleasure. Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia. Glia. 2007;55:57-64 10.1002/glia
- Baxter, 2007 A.G. Baxter. The origin and application of experimental autoimmune encephalomyelitis. Nat. Rev. Immunol.. 2007;7:904-912 10.1038/nri2190
- Behrens et al., 1998 J. Behrens, B.A Jerchow, M. Würtele, J. Grimm, C. Asbrand, R. Wirtz, M. Kühl, D. Wedlich, W. Birchmeier. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280:596-599 10.1126/science.280.5363.596
- Bhatt et al., 2014 A. Bhatt, L. Fan, Y. Pang. Strategies for myelin regeneration: lessons learned from development. Neural Regen. Res.. 2014;9:1347-1350
- Bieber et al., 2003 A.J. Bieber, S. Kerr, M. Rodriguez. Efficient central nervous system remyelination requires T cells. Ann. Neurol.. 2003;53:680-684 10.1002/ana.10578
- Bitsch et al., 2000 A. Bitsch, J. Schuchardt, S. Bunkowski, T. Kuhlmann, W. Brück. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain. 2000;123(Pt 6):1174-1183 10.1093/brain/123.6.1174
- Bjartmar et al., 2000 C. Bjartmar, G. Kidd, S. Mörk, R. Rudick, B.D. Trapp. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann. Neurol.. 2000;48:893-901 10.1002/1531-8249(200012)48 6<893::AID-ANA10>3.0.CO;2-B
- Bjartmar et al., 2003 C. Bjartmar, J.R. Wujek, B.D. Trapp. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J. Neurol. Sci.. 2003;206:165-171 10.1016/S0022-510X(02)00069-2
- Blakemore and Franklin, 2008 W. Blakemore, R. Franklin. Blakemore and Franklin_Curr Top Microbio_2008.pdf. Adv. Mult. Scler. Exp. Demyelinat. Dis. Curr. Top. Microbiol. Immunol.. 2008;318:193-212
- Boyd et al., 2013 A. Boyd, H. Zhang, A. Williams. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol.. 2013;125:841-859 10.1007/s00401-013-1112-y
- Brambilla et al., 2014 R. Brambilla, P.D. Morton, J.J. Ashbaugh, S. Karmally, K.L. Lambertsen, J.R. Bethea. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia. 2014;62:452-467 10.1002/glia.22616
- Brambilla et al., 2009 R. Brambilla, T. Persaud, X. Hu, S. Karmally, V.I. Shestopalov, G. Dvoriantchikova, D. Ivanov, L. Nathanson, S.R. Barnum, J.R. Bethea. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J. Immunol.. 2009;182:2628-2640 10.4049/jimmunol.0802954
- Brinkmann et al., 2008 B.G. Brinkmann, A. Agarwal, M.W. Sereda, A.N. Garratt, T. Müller, H. Wende, R.M. Stassart, S. Nawaz, C. Humml, V. Velanac, K. Radyushkin, S. Goebbels, T.M. Fischer, R.J. Franklin, C. Lai, H. Ehrenreich, C. Birchmeier, M.H. Schwab, K.A. Nave. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron. 2008;59:581-595 10.1016/j.neuron.2008.06.028
- Brosnan and John, 2009 C.F. Brosnan, G.R. John. Revisiting notch in remyelination of multiple sclerosis lesions. J. Clin. Invest.. 2009;119:10-13 10.1172/JCI37786.progressive
- Byravan et al., 1994 S. Byravan, L.M. Foster, T. Phan, A.N. Verity, A.T. Campagnoni. Murine oligodendroglial cells express nerve growth factor. Proc. Natl. Acad. Sci. U. S. A.. 1994;91:8812-8816 10.1073/pnas.91.19.8812
- Campbell et al., 2012 G.R. Campbell, N. Ohno, D.M. Turnbull, D.J. Mahad. Mitochondrial changes within axons in multiple sclerosis: an update. Curr. Opin. Neurol.. 2012;25:221-230 10.1097/WCO.0b013e3283533a25
- Campbell et al., 2014 G.R. Campbell, J.T. Worrall, D.J. Mahad. The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult. Scler. J.. 2014;20:1806-1813 10.1177/1352458514544537
- Carrithers, 2014 M.D. Carrithers. Update on disease-modifying treatments for multiple sclerosis. Clin. Ther.. 2014;36:1938-1945
- Chang et al., 2002 A. Chang, W.W. Tourtellotte, R. Rudick, B.D. Trapp. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med.. 2002;346:165-173 10.1056/NEJMoa010994
- Chapouly et al., 2015 C. Chapouly, a. Tadesse Argaw, S. Horng, K. Castro, J. Zhang, L. Asp, H. Loo, B.M. Laitman, J.N. Mariani, R. Straus Farber, E. Zaslavsky, G. Nudelman, C.S. Raine, G.R. John. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain. 2015;:1548-1567 10.1093/brain/awv077
- Charil et al., 2003 A. Charil, A.P. Zijdenbos, J. Taylor, C. Boelman, K.J. Worsley, A.C. Evans, A. Dagher. Statistical mapping analysis of lesion location and neurological disability in multiple sclerosis: application to 452 patient data sets. Neuroimage. 2003;19:532-544 10.1016/S1053-8119(03)00117-4
- Charles et al., 2000 P. Charles, M.P. Hernandez, B. Stankoff, M.S. Aigrot, C. Colin, G. Rougon, B. Zalc, C. Lubetzki. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc. Natl. Acad. Sci. U. S. A.. 2000;97:7585-7590 10.1073/pnas.100076197
- Charles et al., 2002 P. Charles, R. Reynolds, D. Seilhean, G. Rougon, M.S. Aigrot, A. Niezgoda, B. Zalc, C. Lubetzki. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis?. Brain. 2002;125:1972-1979 10.1093/brain/awf216
- Ciccarelli et al., 2014 O. Ciccarelli, F. Barkhof, B. Bodini, N. De Stefano, X. Golay, K. Nicolay, D. Pelletier, P.J.W. Pouwels, S.A Smith, C.A.M. Wheeler-Kingshott, B. Stankoff, T. Yousry, D.H. Miller. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol.. 2014;13:807-822 10.1016/S1474-4422(14)70101-2
- Colton, 2009 C.A. Colton. Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune Pharmacol.. 2009;4:399-418
- Coman et al., 2006 I. Coman, M.S. Aigrot, D. Seilhean, R. Reynolds, J.A. Girault, B. Zalc, C. Lubetzki. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain. 2006;129:3186-3195 10.1093/brain/awl144
- Compston and Coles, 2008 A. Compston, A. Coles. Multiple sclerosis. Lancet. 2008;372:1502-1517 10.1016/S0140-6736(08)61620-7
- Copelman et al., 2001 C.A. Copelman, L.T. Diemel, D. Gveric, N.A. Gregson, M. Louise Cuzner. Myelin phagocytosis and remyelination of macrophage-enriched central nervous system aggregate cultures. J. Neurosci. Res.. 2001;66:1173-1178 10.1002/jnr.10026
- Craner et al., 2004 M. Craner, B.C. Hains, A.C. Lo, J.A Black, S.G. Waxman. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain. 2004;127:294-303 10.1093/brain/awh032
- D'Souza et al., 2008 B. D'Souza, A. Miyamoto, G. Weinmaster. The many facets of notch ligands. Oncogene. 2008;27:5148-5167 10.1038/onc.2008.229
- Dai et al., 2003 X. Dai, L.D. Lercher, P.M. Clinton, Y. Du, D.L. Livingston, C. Vieira, L. Yang, M.M. Shen, C.F. Dreyfus. The trophic role of oligodendrocytes in the basal forebrain. J. Neurosci.. 2003;23:5846-5853
- Dai et al., 2014 Z. Dai, S. Sun, C. Wang, H. Huang, X. Hu, Z. Zhang, Q.R. Lu, M. Qiu. Stage-specific regulation of oligodendrocyte development by Wnt/β-catenin signaling. J. Neurosci.. 2014;34:8467-8473 10.1523/JNEUROSCI.0311-14.2014
- Dawson et al., 2003 M.R.L. Dawson, A. Polito, J.M. Levine, R. Reynolds. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol. Cell. Neurosci.. 2003;24:476-488 10.1016/S1044-7431(03)00210-0
- Denic et al., 2011 a Denic, A. Johnson, A. Bieber. The relevance of animal models in multiple sclerosis research. Pathophysiology. 2011;18:1-16 10.1016/j.pathophys.2010.04.004.The
- Denney et al., 2012 L. Denney, W.L. Kok, S.L. Cole, S. Sanderson, A.J. McMichael, L.-P. Ho. Activation of invariant NKT cells in early phase of experimental autoimmune encephalomyelitis results in differentiation of Ly6Chi inflammatory monocyte to M2 macrophages and improved outcome. J. Immunol.. 2012;189:551-557 10.4049/jimmunol.1103608
- Deshmukh et al., 2013 V. Deshmukh, V. Tardif, C. Lyssiotis, C. Green, B. Kerman, H.J. Kim, K. Padmanabhan, J.G. Swoboda, I. Ahmad, T. Kondo, F.H. Gage, a N. Theofilopoulos, B.R. Lawson, P.G. Schultz, L.L. Lairson. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013;502:327-332 10.1038/nature12647
- Dougherty et al., 2000 K.D. Dougherty, C.F. Dreyfus, I.B. Black. Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol. Dis.. 2000;7:574-585 10.1006/nbdi.2000.0318
- Dutta and Trapp, 2011 R. Dutta, B.D. Trapp. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog. Neurobiol.. 2011;93:1-12 10.1016/j.pneurobio.2010.09.005
- Dziedzic et al., 2010 T. Dziedzic, I. Metz, T. Dallenga, F.B. König, S. Müller, C. Stadelmann, W. Brück. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol.. 2010;20:976-985 10.1111/j.1750-3639.2010.00401.x
- Edgar et al., 2010 J.M. Edgar, M.C. McCulloch, P. Montague, A.M. Brown, S. Thilemann, L. Pratola, F.I. Gruenenfelder, I.R. Griffiths, K.-A. Nave. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease. EMBO Mol. Med.. 2010;2:42-50 10.1002/emmm.200900057
- Edgar et al., 2009 J.M. Edgar, M. McLaughlin, H.B. Werner, M.C. McCulloch, J.A. Barrie, A. Brown, A.B. Faichney, N. Snaidero, K.-A. Nave, I.R. Griffiths. Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Glia. 2009;57:1815-1824 10.1002/glia.20893
- England et al., 1990 J.D. England, F. Gamboni, S.R. Levinson, T.E. Finger. Changed distribution of sodium channels along demyelinated axons. Proc. Natl. Acad. Sci. U. S. A.. 1990;87:6777-6780 10.1073/pnas.87.17.6777
- Eshleman et al., 1994 a J. Eshleman, R.A. Henningsen, K.A. Neve, A Janowsky. Release of dopamine via the human transporter. Mol. Pharmacol.. 1994;45:312-316
- Fancy et al., 2009 S.P.J. Fancy, S.E. Baranzini, C. Zhao, D.I. Yuk, K.A. Irvine, S. Kaing, N. Sanai, R.J.M. Franklin, D.H. Rowitch. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev.. 2009;23:1571-1585 10.1101/gad.1806309
- Fancy et al., 2011a S.P.J. Fancy, J.R. Chan, S.E. Baranzini, R.J.M. Franklin, D.H. Rowitch. Myelin regeneration: a recapitulation of development?. Annu. Rev. Neurosci.. 2011;34:21-43 10.1146/annurev-neuro-061010-113629
- Fancy et al., 2014 S.P.J. Fancy, E.P. Harrington, S.E. Baranzini, J.C. Silbereis, L.R. Shiow, T.J. Yuen, E.J. Huang, S. Lomvardas, D.H. Rowitch. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer. Nat. Neurosci.. 2014;17:506-512 10.1038/nn.3676
- Fancy et al., 2011b S.P.J. Fancy, E.P. Harrington, T.J. Yuen, J.C. Silbereis, C. Zhao, S.E. Baranzini, C.C. Bruce, J.J. Otero, E.J. Huang, R. Nusse, R.J.M. Franklin, D.H. Rowitch. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat. Neurosci.. 2011;14:1009-1016 10.1038/nn.2855
- Fancy et al., 2010 S.P.J. Fancy, M.R. Kotter, E.P. Harrington, J.K. Huang, C. Zhao, D.H. Rowitch, R.J.M. Franklin. Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp. Neurol.. 2010;225:18-23 10.1016/j.expneurol.2009.12.020
- Ferguson et al., 1997 B. Ferguson, M.K. Matyszak, M.M. Esiri, V.H. Perry. Axonal damage in acute multiple sclerosis lesions. Brain. 1997;120(3):393-399 10.1093/brain/120.3.393
- Fischer et al., 2012 M.T. Fischer, R. Sharma, J.L. Lim, L. Haider, J.M. Frischer, J. Drexhage, D. Mahad, M. Bradl, J. van Horssen, H. Lassmann. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135:886-899 10.1093/brain/aws012
- Fisher et al., 2002 E. Fisher, R.A. Rudick, J.H. Simon, G. Cutter, M. Baier, J.-C. Lee, D. Miller, B. Weinstock-Guttman, M.K. Mass, D.S. Dougherty, N. a Simonian. Eight-year follow-up study of brain atrophy in patients with MS. Neurology. 2002;59:1412-1420 10.1212/01.WNL.0000036271.49066.06
- Frankenhaeuser, 1952 B. Frankenhaeuser. Saltatory conduction in myelinated nerve fibres. J. Physiol.. 1952;118:107-112
- Franklin, 2002 R.J.M. Franklin. Why does remyelination fail in multiple sclerosis?. Nat. Rev. Neurosci.. 2002;3:705-714 10.1038/nrn917
- Franklin and Ffrench-Constant, 2008 R.J.M. Franklin, C. ffrench-Constant. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci.. 2008;9:839-855 10.1038/nrn2480
- Fu et al., 2009 H. Fu, J. Cai, H. Clevers, E. Fast, S. Gray, R. Greenberg, M.K. Jain, Q. Ma, M. Qiu, D.H. Rowitch, C.M. Taylor, C.D. Stiles. A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development. J. Neurosci.. 2009;29:11399-11408 10.1523/JNEUROSCI.0160-09.2009
- Fünfschilling et al., 2012 U. Fünfschilling, L.M. Supplie, D. Mahad, S. Boretius, A.S. Saab, J. Edgar, B.G. Brinkmann, C.M. Kassmann, I.D. Tzvetanova, W. Möbius, F. Diaz, D. Meijer, U. Suter, B. Hamprecht, M.W. Sereda, C.T. Moraes, J. Frahm, S. Goebbels, K.-A. Nave. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485:517-521 10.1038/nature11007
- Gadea et al., 2009 A. Gadea, A. Aguirre, T.F. Haydar, V. Gallo. Endothelin-1 regulates oligodendrocyte development. J. Neurosci.. 2009;29:10047-10062 10.1523/jneurosci.0822-09.2009
- Gadea et al., 2008 A. Gadea, S. Schinelli, V. Gallo. Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J. Neurosci.. 2008;28:2394-2408 10.1523/jneurosci.5652-07.2008
- Genoud et al., 2002 S. Genoud, C. Lappe-Siefke, S. Goebbels, F. Radtke, M. Aguet, S.S. Scherer, U. Suter, K.A. Nave, N. Mantei. Notch1 control of oligodendrocyte differentiation in the spinal cord. J. Cell Biol.. 2002;158:709-718 10.1083/jcb.200202002
- Giraudon et al., 2004 P. Giraudon, P. Vincent, C. Vuaillat, O. Verlaeten, L. Cartier, A. Marie-Cardine, M. Mutin, A. Bensussan, M.-F. Belin, L. Boumsell. Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. J. Immunol.. 2004;172:1246-1255
- Givogri et al., 2002 M.I. Givogri, R.M. Costa, V. Schonmann, A.J. Silva, A.T. Campagnoni, E.R. Bongarzone. Central nervous system myelination in mice with deficient expression of Notch1 receptor. J. Neurosci. Res.. 2002;67:309-320 10.1002/jnr.10128
- Goldschmidt et al., 2009 T. Goldschmidt, J. Antel, F.B. König, W. Brück, T. Kuhlmann. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology. 2009;72:1914-1921 10.1212/WNL.0b013e3181a8260a
- Gonzalez et al., 1990 D. Gonzalez, W. Dees, J. Hiney, S. Ojeda, R. Saneto. Expression of beta-nerve growth factor in cultured cells derived from the hypothalamus and cerebral cortex. Brain Res.. 1990;511:249-258
- Gray et al., 2012 E. Gray, C. Rice, H. Nightingale, M. Ginty, K. Hares, K. Kemp, N. Cohen, S. Love, N. Scolding, A. Wilkins. Accumulation of cortical hyperphosphorylated neurofilaments as a marker of neurodegeneration in multiple sclerosis. Mult. Scler. J.. 2012;19:153-161 10.1177/1352458512451661
- Griffiths et al., 1998 I. Griffiths, M. Klugmann, T. Anderson, D. Yool, C. Thomson, M. Schwab, A. Schneider, F. Zimmerman, M. McCulloch, N. Nadon, K.-A. Nave. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science. 1998;280(80):1610-1613 10.1126/science.280.5369.1610
- Guo et al., 2015 F. Guo, J. Lang, J. Sohn, E. Hammond, M. Chang, D. Pleasure. Canonical Wnt signaling in the oligodendroglial lineage-puzzles remain. Glia. 2015;63:1671-1693 10.1002/glia.22813
- Haines et al., 2011 J. Haines, M. Inglese, P. Casaccia. Axonal damage in multiple sclerosis. Mt. Sinai J. Med.. 2011;78:231-243 10.1002/MSJ
- Haines et al., 2009 J.D. Haines, M. Inglese, P. Casaccia. Axonal damage in multiple sclerosis. Mt. Sinai J. Med.. 2009;76:173-181 10.1002/MSJ
- Hammond et al., 2014 T.R. Hammond, A. Gadea, J. Dupree, C. Kerninon, B. Nait-oumesmar, A. Aguirre. Astrocyte-derived endothelin-1 inhibits remyelination through notch activation. Neuron. 2014;81:588-602
- Hartline and Colman, 2007 D.K. Hartline, D.R. Colman. Rapid conduction and the evolution of giant axons and myelinated fibers. Curr. Biol.. 2007;17:29-35 10.1016/j.cub.2006.11.042
- Hinks and Franklin, 1999 G.L. Hinks, R.J. Franklin. Distinctive patterns of PDGF-A, FGF-2, IGF-I, and TGF-beta1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Mol. Cell. Neurosci.. 1999;14:153-168 10.1006/mcne.1999.0771
- Horner et al., 2002 P.M.T. Horner, et al. Defining the NG2-expressing cell of the adult CNS. J. Neurocytol.. 2002;31:469-480
- Huang and Franklin, 2011 J.K. Huang, R.J.M. Franklin. Regenerative medicine in multiple sclerosis: identifying pharmacological targets of adult neural stem cell differentiation. Neurochem. Int.. 2011;59:329-332 10.1016/j.neuint.2011.01.017
- Huang et al., 2011 J.K. Huang, A. a Jarjour, B. Nait Oumesmar, C. Kerninon, A. Williams, W. Krezel, H. Kagechika, J. Bauer, C. Zhao, A. Baron-Van Evercooren, P. Chambon, C. Ffrench-Constant, R.J.M. Franklin. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci.. 2011;14:45-53 10.1038/nn.2702
- Irvine and Blakemore, 2008 K.A. Irvine, W.F. Blakemore. Remyelination protects axons from demyelination-associated axon degeneration. Brain. 2008;131:1464-1477 10.1093/brain/awn080
- Jeffery and Blakemore, 1997 N.D. Jeffery, W.F. Blakemore. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain. 1997;120:27-37 10.1093/brain/120.1.27
- Jho et al., 2002 E. Jho, T. Zhang, C. Domon, C. Joo, J. Freund, F. Costantini. Wnt/β -catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway Wnt/NL – catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol. Cell. Biol.. 2002;22:1172-1183 10.1128/MCB.22.4.1172
- Ji et al., 2006 B. Ji, M. Li, W.T. Wu, L.W. Yick, X. Lee, Z. Shao, J. Wang, K.F. So, J.M. McCoy, R. Blake Pepinsky, S. Mi, J.K. Relton. LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. Mol. Cell. Neurosci.. 2006;33:311-320 10.1016/j.mcn.2006.08.003
- John et al., 2002 G. John, S. Shankar, B. Shafit-Zagardo, A. Massimi, S. Lee, C. Raine, C. Brosnan. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat. Med.. 2002;8:1115-1121 10.1038/nm
- Jongbloets and Pasterkamp, 2014 B.C. Jongbloets, R.J. Pasterkamp. Semaphorin signalling during development. Development. 2014;141:3292-3297 10.1242/dev.105544
- Joshi et al., 2015 D.C. Joshi, C.-L. Zhang, T.-M. Lin, a. Gusain, M.G. Harris, E. Tree, Y. Yin, C. Wu, Z.-H. Sheng, R.J. Dempsey, Z. Fabry, S.Y. Chiu. Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS. J. Neurosci.. 2015;35:5293-5306 10.1523/JNEUROSCI.3859-14.2015
- Katsumoto et al., 2014 a. Katsumoto, H. Lu, a. S. Miranda, R.M. Ransohoff. Ontogeny and functions of central nervous system macrophages. J. Immunol.. 2014;193:2615-2621 10.4049/jimmunol.1400716
- Katzenschlager et al., 2003 R. Katzenschlager, C. Sampaio, J. Costa, A. Lees. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst. Rev.. 2003;2 10.1002/14651858.CD003735
- Kim et al., 2003 J.Y. Kim, Q. Sun, M. Oglesbee, S.O. Yoon. The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. J. Neurosci.. 2003;23:5561-5571 doi:23/13/5561
- Kiryu-Seo et al., 2010 S. Kiryu-Seo, N. Ohno, G.J. Kidd, H. Komuro, B.D. Trapp. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J. Neurosci.. 2010;30:6658-6666 10.1523/JNEUROSCI.5265-09.2010
- Klaver et al., 2015 R. Klaver, V. Popescu, P. Voorn, Y.G. Graaf, P. Valk, H.E. Van Der Vries, G.J. De Schenk, J.J.G. Geurts. Neuronal and axonal loss in normal-appearing gray matter and subpial lesions in multiple sclerosis. J. Neuropathol. Exp. Neurol.. 2015;74:453-458
- Kornek et al., 2000 B. Kornek, M.K. Storch, R. Weissert, E. Wallstroem, a Stefferl, T. Olsson, C. Linington, M. Schmidbauer, H. Lassmann. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol.. 2000;157:267-276 10.1016/S0002-9440(10)64537-3
- Kotter et al., 2006 M.R. Kotter, W.-W. Li, C. Zhao, R.J.M. Franklin. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci.. 2006;26:328-332 10.1523/JNEUROSCI.2615-05.2006
- Kotter et al., 2005 M.R. Kotter, C. Zhao, N. Van Rooijen, R.J.M. Franklin. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol. Dis.. 2005;18:166-175 10.1016/j.nbd.2004.09.019
- Kuhlmann et al., 2008 T. Kuhlmann, V. Miron, Q. Cuo, C. Wegner, J. Antel, W. Brück. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain. 2008;131:1749-1758 10.1093/brain/awn096
- Lang and Lees, 2002 A. Lang, A. Lees. Management of Parkinson's disease: an evidence based review. Mov. Disord.. 2002;17:S1-S6 10.1002/mds.5555
- Lang et al., 2013 J. Lang, Y. Maeda, P. Bannerman, J. Xu, M. Horiuchi, D. Pleasure, F. Guo. Adenomatous polyposis coli regulates oligodendroglial development. J. Neurosci.. 2013;33:3113-3130 10.1523/JNEUROSCI.3467-12.2013
- Langmead et al., 2008 C.J. Langmead, J. Watson, C. Reavill. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol. Ther.. 2008;117:232-243 10.1016/j.pharmthera.2007.09.009
- Lappe-Siefke et al., 2003 C. Lappe-Siefke, S. Goebbels, M. Gravel, E. Nicksch, J. Lee, P.E. Braun, I.R. Griffiths, K.-A. Nave. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet.. 2003;33:366-374 10.1038/ng1095
- Lassmann, 2014 H. Lassmann. Mechanisms of white matter damage in multiple sclerosis. Glia. 2014;62:1816-1830 10.1002/glia.22597
- Le et al., 2014 P.N. Le, J.D. Mcdermott, A. Jimeno. Pharmacology & therapeutics targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol. Ther.. 2014;146C:1-11
- Lee et al., 2015 H.K. Lee, L.S. Chaboub, S.P.J. Fancy, B. Deneen, H.K. Lee, L.S. Chaboub, W. Zhu, D. Zollinger, M.N. Rasband, S.P.J. Fancy. Daam2-PIP5K is a regulatory pathway for wnt signaling and therapeutic target for remyelination in the CNS. Neuron. 2015;85:1227-1243
- Lee et al., 2014 X. Lee, Z. Shao, G. Sheng, B. Pepinsky, S. Mi. LINGO-1 regulates oligodendrocyte differentiation by inhibiting ErbB2 translocation and activation in lipid rafts. Mol. Cell. Neurosci.. 2014;60:36-42 10.1016/j.mcn.2014.02.006
- Lee et al., 2007 X. Lee, Z. Yang, Z. Shao, S.S. Rosenberg, M. Levesque, R.B. Pepinsky, M. Qiu, R.H. Miller, J.R. Chan, S. Mi. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. J. Neurosci.. 2007;27:220-225 10.1523/JNEUROSCI.4175-06.2007
- Lee et al., 2012 Y. Lee, B.M. Morrison, Y. Li, S. Lengacher, M.H. Farah, P.N. Hoffman, Y. Liu, A. Tsingalia, L. Jin, P.-W. Zhang, L. Pellerin, P.J. Magistretti, J.D. Rothstein. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487:443-448 10.1038/nature11314
- Lees, 2005 A. Lees. Alternatives to levodopa in the initial treatment of early Parkinson's disease. Drugs Aging. 2005;22:731-740
- Li et al., 2009 H. Li, Y. He, W.D. Richardson, P. Casaccia. Two-tier transcriptional control of oligodendrocyte differentiation. Curr. Opin. Neurobiol.. 2009;19:479-485 10.1016/j.conb.2009.08.004
- Lucchinetti et al., 1999 C. Lucchinetti, W. Brück, J. Parisi, B. Scheithauer, M. Rodriguez, H. Lassmann. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain. 1999;122:2279-2295 10.1093/brain/122.12.2279
- Mahad et al., 2008 D. Mahad, I. Ziabreva, H. Lassmann, D. Turnbull. Mitochondrial defects in acute multiple sclerosis lesions. Brain. 2008;131:1722-1735 10.1093/brain/awn105
- Mahad et al., 2015 D.H. Mahad, B.D. Trapp, H. Lassmann. Series Progressive Multiple Sclerosis 1 Pathological Mechanisms in Progressive Multiple Sclerosis C. (, 2015) 183-193
- Mahad et al., 2009 D.J. Mahad, I. Ziabreva, G. Campbell, N. Lax, K. White, P.S. Hanson, H. Lassmann, D.M. Turnbull. Mitochondrial changes within axons in multiple sclerosis. Brain. 2009;132:1161-1174 10.1093/brain/awp046
- Makinodan et al., 2012 M. Makinodan, K.M. Rosen, S. Ito, G. Corfas. A critical period for social experience – dependent oligodendrocyte maturation and myelination period for social experience. Science. 2012;337(80):1357-1360
- Mantovani et al., 2013 A. Mantovani, S.K. Biswas, M.R. Galdiero, A. Sica, M. Locati. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol.. 2013;229:176-185
- Mark et al., 2009 M. Mark, N.B. Ghyselinck, P. Chambon. Function of retinoic acid receptors during embryonic development. Nucl. Recept. Signal. 2009;7:e002 10.1621/nrs.07002
- Mason et al., 2001 J.L. Mason, K. Suzuki, D.D. Chaplin, G.K. Matsushima. Interleukin-1beta promotes repair of the CNS. J. Neurosci.. 2001;21:7046-7052 doi:21/18/7046
- Mayo et al., 2014 L. Mayo, S. a Trauger, M. Blain, M. Nadeau, B. Patel, J.I. Alvarez, I.D. Mascanfroni, A. Yeste, P. Kivisäkk, K. Kallas, B. Ellezam, R. Bakshi, A. Prat, J.P. Antel, H.L. Weiner, F.J. Quintana. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med.. 2014;20 10.1038/nm.3681
- McKearney, 1982 J. McKearney. Stimulant actions of histamine H1 antagonists on operant behavior in the squirrel monkey. Psychopharmacol. (Berl.). 1982;77:156-158
- Mei et al., 2014 F. Mei, S.P.J. Fancy, Y.-A. A. Shen, J. Niu, C. Zhao, B. Presley, E. Miao, S. Lee, S.R. Mayoral, S. a Redmond, A. Etxeberria, L. Xiao, R.J.M. Franklin, A. Green, S.L. Hauser, J.R. Chan. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med.. 2014;20:954-960 10.1038/nm.3618
- Mews et al., 1998 I. Mews, M. Bergmann, S. Bunkowski, F. Gullotta, W. Brück. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult. Scler.. 1998;4:55-62 10.1191/135245898678919582
- Mi et al., 2007 S. Mi, B. Hu, K. Hahm, Y. Luo, E.S. Kam Hui, Q. Yuan, W.M. Wong, L. Wang, H. Su, T.-H. Chu, J. Guo, W. Zhang, K.-F. So, B. Pepinsky, Z. Shao, C. Graff, E. Garber, V. Jung, E.X. Wu, W. Wu. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med.. 2007;13:1228-1233 10.1038/nm1664
- Mi et al., 2005 S. Mi, R.H. Miller, X. Lee, M.L. Scott, S. Shulag-Morskaya, Z. Shao, J. Chang, G. Thill, M. Levesque, M. Zhang, C. Hession, D. Sah, B. Trapp, Z. He, V. Jung, J.M. McCoy, R.B. Pepinsky. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci.. 2005;8:745-751 10.1038/nn1460
- Mi et al., 2009 S. Mi, R.H. Miller, W. Tang, X. Lee, B. Hu, W. Wu, Y. Zhang, C.B. Shields, Y. Zhang, S. Miklasz, D. Shea, J. Mason, R.J.M. Franklin, B. Ji, Z. Shao, A. Chédotal, F. Bernard, A. Roulois, J. Xu, V. Jung, B. Pepinsky. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann. Neurol.. 2009;65:304-315 10.1002/ana.21581
- Mikita et al., 2011 J. Mikita, N. Dubourdieu-Cassagno, M.S. Deloire, A. Vekris, M. Biran, G. Raffard, B. Brochet, M.-H. Canron, J.-M. Franconi, C. Boiziau, K.G. Petry. Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult. Scler.. 2011;17:2-15 10.1177/1352458510379243
- Milo and Kahana, 2010 R. Milo, E. Kahana. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun. Rev.. 2010;9 10.1016/j.autrev.2009.11.010
- Miron et al., 2013 V.E. Miron, A. Boyd, J.-W. Zhao, T.J. Yuen, J.M. Ruckh, J.L. Shadrach, P. van Wijngaarden, A.J. Wagers, A. Williams, R.J.M. Franklin, C. ffrench-Constant. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci.. 2013;16:1211-1218 10.1038/nn.3469
- Mutsaers and Carroll, 1998 S.E. Mutsaers, W.M. Carroll. Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve. Acta Neuropathol.. 1998;96:139-143
- Nave, 2010 K.-A. Nave. Myelination and the trophic support of long axons. Nat. Rev. Neurosci.. 2010;11:275-283 10.1038/nrn2797
- Nave and Trapp, 2008 K.-A. Nave, B.D. Trapp. Axon-glial signaling and the glial support of axon function. Annu. Rev. Neurosci.. 2008;31:535-561 10.1146/annurev.neuro.30.051606.094309
- Nikić et al., 2011 I. Nikić, D. Merkler, C. Sorbara, M. Brinkoetter, M. Kreutzfeldt, F.M. Bareyre, W. Brück, D. Bishop, T. Misgeld, M. Kerschensteiner. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med.. 2011;17:495-499 10.1038/nm.2324
- Oluich et al., 2012 L.-J. Oluich, J.A.S. Stratton, Y.L. Xing, S.W. Ng, H.S. Cate, P. Sah, F. Windels, T.J. Kilpatrick, T.D. Merson. Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. J. Neurosci.. 2012;32:8317-8330 10.1523/JNEUROSCI.1053-12.2012
- Ortega et al., 2013 F. Ortega, S. Gascón, G. Masserdotti, A. Deshpande, C. Simon, J. Fischer, L. Dimou, D. Chichung Lie, T. Schroeder, B. Berninger. Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling. Nat. Cell Biol.. 2013;15:602-613 10.1038/ncb2736
- Ousman and David, 2000 S.S. Ousman, S. David. Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia. 2000;30:92-104
- Pachner, 2011 A.R. Pachner. Experimental models of multiple sclerosis. Curr. Opin. Neurol.. 2011;24:291-299 10.1097/WCO.0b013e328346c226
- Park et al., 2001 S.K. Park, R. Miller, I. Krane, T. Vartanian. The ErbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes. J. Cell Biol.. 2001;154:1245-1258 10.1083/jcb.200104025
- Patrikios et al., 2006 P. Patrikios, C. Stadelmann, A. Kutzelnigg, H. Rauschka, M. Schmidbauer, H. Laursen, P.S. Sorensen, W. Brück, C. Lucchinetti, H. Lassmann. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006;129:3165-3172 10.1093/brain/awl217
- Pedraza et al., 2001 L. Pedraza, J.K. Huang, D.R. Colman. Organizing principles of the axoglial apparatus. Neuron. 2001;30:335-344
- Petzold et al., 2008 A. Petzold, D. Gveric, M. Groves, K. Schmierer, D. Grant, M. Chapman, G. Keir, L. Cuzner, E.J. Thompson. Phosphorylation and compactness of neurofilaments in multiple sclerosis: Indicators of axonal pathology. Exp. Neurol.. 2008;213:326-335 10.1016/j.expneurol.2008.06.008
- Piaton et al., 2011 G. Piaton, M.S. Aigrot, A. Williams, S. Moyon, V. Tepavcevic, I. Moutkine, J. Gras, K.S. Matho, A. Schmitt, H. Soellner, A.B. Huber, P. Ravassard, C. Lubetzki. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain. 2011;134:1156-1167 10.1093/brain/awr022
- Podbielska et al., 2013 M. Podbielska, N.L. Banik, E. Kurowska, E.L. Hogan. Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci.. 2013;3:1282-1324 10.3390/brainsci3031282
- Pringle et al., 1992 N.P. Pringle, H.S. Mudhar, E.J. Collarini, W.D. Richardson. PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development. 1992;115:535-551
- Qi et al., 2006 X. Qi, A.S. Lewin, L. Sun, W.W. Hauswirth, J. Guy. Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J. Biol. Chem.. 2006;281:31950-31962 10.1074/jbc.M603717200
- Ransohoff, 2012 R.M. Ransohoff. Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat. Neurosci.. 2012;15:1074-1077 10.1038/nn.3168
- Rasband, 2008 M.N. Rasband. Na+ channels get anchored...with a little help. J. Cell Biol.. 2008;183:975-977 10.1083/jcb.200811086
- Rasband, 2010 M.N. Rasband. Clustered K+ channel complexes in axons. Neurosci. Lett.. 2010;486:101-106 10.1016/j.neulet.2010.08.081
- Rastinejad, 2001 F. Rastinejad. Retinoid X receptor and its partners in the nuclear receptor family. Curr. Opin. Struct. Biol.. 2001;11:33-38 10.1016/S0959-440X(00)00165-2
- Rice, 2014 C.M. Rice. Disease modification in multiple sclerosis: an update. Pract. Neurol.. 2014;14:6-13 10.1136/practneurol-2013-000601
- Robinson and Miller, 1999 S. Robinson, R. Miller. Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev. Biol.. 1999;216:359-368
- Rodriguez et al., 2014 J.P. Rodriguez, M. Coulter, J. Miotke, R.L. Meyer, K.-I. Takemaru, J.M. Levine. Abrogation of b-catenin signaling in oligodendrocyte precursor cells reduces glial Scarring and promotes axon regeneration after CNS injury. J. Neurosci.. 2014;34:10285-10297 10.1523/JNEUROSCI.4915-13.2014
- Rodriguez, 2007 M. Rodriguez. Effectors of demyelination and remyelination in the CNS: Implications for multiple sclerosis. Brain Pathol.. 2007;17:219-229 10.1111/j.1750-3639.2007.00065.x
- Ruckh et al., 2012 J. Ruckh, J. Zhao, J. Shadrach, P. van Wijngaarden, T. Rao, A. Wagers, R. Franklin. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell. 2012;10:96-103 10.1016/j.biotechadv.2011.08.021.Secreted
- Rudick et al., 1999 R.A. Rudick, E. Fisher, J.C. Lee, J. Simon, L. Jacobs. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999;53:1698-1704 10.1212/WNL.53.8.1698
- Rudick et al., 2008 R.A. Rudick, S. Mi, A.W. Sandrock. LINGO-1 antagonists as therapy for multiple sclerosis: in vitro and in vivo evidence. Expert Opin. Biol. Ther.. 2008;8:1561-1570 10.1517/14712522.214.171.1241
- Saab et al., 2013 A.S. Saab, I.D. Tzvetanova, K.A. Nave. The role of myelin and oligodendrocytes in axonal energy metabolism. Curr. Opin. Neurobiol.. 2013;23:1065-1072 10.1016/j.conb.2013.09.008
- Sailer et al., 2003 M. Sailer, B. Fischl, D. Salat, C. Tempelmann, M.A. Schönfeld, E. Busa, N. Bodammer, H.J. Heinze, A. Dale. Focal thinning of the cerebral cortex in multiple sclerosis. Brain. 2003;126:1734-1744 10.1093/brain/awg175
- Saxena and Caroni, 2007 S. Saxena, P. Caroni. Mechanisms of axon degeneration: from development to disease. Prog. Neurobiol.. 2007;83:174-191 10.1016/j.pneurobio.2007.07.007
- Scherer and Arroyo, 2002 S.S. Scherer, E.J. Arroyo. Recent progress on the molecular organization of myelinated axons. J. Peripher. Nerv. Syst.. 2002;7:1-12
- Schirmer et al., 2011 L. Schirmer, J.P. Antel, W. Brück, C. Stadelmann. Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis. Brain Pathol.. 2011;21:428-440 10.1111/j.1750-3639.2010.00466.x
- Seifert et al., 2007 T. Seifert, J. Bauer, R. Weissert, F. Fazekas, M.K. Storch. Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination. Acta Neuropathol.. 2007;113:195-203 10.1007/s00401-006-0170-9
- Shechter and Schwartz, 2013 R. Shechter, M. Schwartz. Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer if’ but how. J. Pathol.. 2013;229:332-346 10.1002/path.4106
- Shimizu et al., 2005 T. Shimizu, T. Kagawa, T. Wada, Y. Muroyama, S. Takada, K. Ikenaka. Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Dev. Biol.. 2005;282:397-410 10.1016/j.ydbio.2005.03.020
- Sim et al., 2002 F.J. Sim, C. Zhao, J. Penderis, R.J.M. Franklin. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J. Neurosci.. 2002;22:2451-2459 10.1097/00041327-200306000-00025
- Smith et al., 2015 E.S. Smith, A. Jonason, C. Reilly, J. Veeraraghavan, T. Fisher, M. Doherty, E. Klimatcheva, C. Mallow, C. Cornelius, J.E. Leonard, N. Marchi, D. Janigro, A. Tadesse, T. Pham, J. Seils, H. Bussler, S. Torno, R. Kirk, A. Howell, E.E. Evans, M. Paris, W.J. Bowers, G. John, M. Zauderer. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol. Dis.. 2015;73:254-268
- Smith et al., 1979 K. Smith, W. Blakemore, W. McDonald. Central remyelination restores secure conduction. Nature. 1979;280:395-396
- Sofroniew, 2009 M.V. Sofroniew. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci.. 2009;32:638-647 10.1016/j.tins.2009.08.002
- Sosa et al., 2013 R.A. Sosa, C. Murphey, N. Ji, A.E. Cardona, T.G. Forsthuber. The kinetics of myelin antigen uptake by myeloid cells in the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol.. 2013;191:5848-5857 10.4049/jimmunol.1300771
- Spassky et al., 2002 N. Spassky, F. de Castro, B. Le Bras, K. Heydon, F. Quéraud-LeSaux, E. Bloch-Gallego, A. Chédotal, B. Zalc, J.-L. Thomas. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J. Neurosci.. 2002;22:5992-6004 doi:20026573
- Sriram and Steiner, 2005 S. Sriram, I. Steiner. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann. Neurol.. 2005;58:939-945 10.1002/ana.20743
- Stidworthy et al., 2004 M.F. Stidworthy, S. Genoud, W.W. Li, D.P. Leone, N. Mantei, U. Suter, R.J.M. Franklin. Notch1 and jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination. Brain. 2004;127:1928-1941 10.1093/brain/awh217
- Stolt et al., 2002 C.C. Stolt, S. Rehberg, M. Ader, P. Lommes, D. Riethmacher, M. Schachner, U. Bartsch, M. Wegner. Terminal Differentiation of Myelin-forming Oligodendrocytes Depends on the Transcription Factor Sox10 Service Terminal Differentiation of Myelin-forming Oligodendrocytes Depends on the Transcription Factor Sox10. (, 2002) 165-170 10.1101/gad.215802
- Sugimoto et al., 2001 Y. Sugimoto, M. Taniguchi, T. Yagi, Y. Akagi, Y. Nojyo, N. Tamamaki. Guidance of glial precursor cell migration by secreted cues in the developing optic nerve. Development. 2001;128:3321-3330
- Sussman et al., 2005 C.R. Sussman, T. Vartanian, R.H. Miller. The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation. J. Neurosci.. 2005;25:5757-5762 10.1523/JNEUROSCI.4748-04.2005
- Syed et al., 2011 Y.A. Syed, E. Hand, W. Möbius, C. Zhao, M. Hofer, K.A. Nave, M.R. Kotter. Inhibition of CNS remyelination by the presence of semaphorin 3A. J. Neurosci.. 2011;31:3719-3728 10.1523/JNEUROSCI.4930-10.2011
- Tanaka and Yoshida, 2014 T. Tanaka, S. Yoshida. Mechanisms of remyelination: recent insight from experimental models. Biomol. Concepts. 2014;5:289-298 10.1515/bmc-2014-0015
- Tawk et al., 2011 M. Tawk, J. Makoukji, M. Belle, C. Fonte, A. Trousson, T. Hawkins, H. Li, S. Ghandour, M. Schumacher, C. Massaad. Wnt/beta-catenin signaling is an essential and direct driver of myelin gene expression and myelinogenesis. J. Neurosci.. 2011;31:3729-3742 10.1523/JNEUROSCI.4270-10.2011
- Traka et al., 2010 M. Traka, K. Arasi, R.L. Avila, J.R. Podojil, A. Christakos, S.D. Miller, B. Soliven, B. Popko. A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain. 2010;133:3017-3029 10.1093/brain/awq247
- Trapp and Nave, 2008 B.D. Trapp, K.-A. Nave. Multiple sclerosis: an immune or neurodegenerative disorder?. Annu. Rev. Neurosci.. 2008;31:247-269 10.1146/annurev.neuro.30.051606.094313
- Trapp et al., 1998 B.D. Trapp, J. Peterson, R.M. Ransohoff, R. Rudick, S. Mörk, L. Bö. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med.. 1998;338:278-285 10.1056/NEJM199801293380502
- Trapp and Stys, 2009 B.D. Trapp, P.K. Stys. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol.. 2009;8:280-291 10.1016/S1474-4422(09)70043-2
- Tran et al., 2014 J.Q. Tran, J. Rana, F. Barkhof, I. Melamed, H. Gevorkyan, M.P. Wattjes, R. de Jong, K. Brosofsky, S. Ray, L. Xu, J. Zhao, E. Parr, D. Cadavid. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol. Neuroimmunol. Neuroinflamm.. 2014;1:e18
- Van Wijngaarden and Franklin, 2013 P. Van Wijngaarden, R.J.M. Franklin. Ageing stem and progenitor cells: implications for rejuvenation of the central nervous system. Development. 2013;140:2562-2575 10.1242/dev.092262
- Vela et al., 2002 J.M. Vela, E. Molina-Holgado, A. Arévalo-Martín, G. Almazán, C. Guaza. Interleukin-1 regulates proliferation and differentiation of oligodendrocyte progenitor cells. Mol. Cell. Neurosci.. 2002;20:489-502 10.1006/mcne.2002.1127
- Wang et al., 1998 S. Wang, A.D. Sdrulla, G. DiSibio, G. Bush, D. Nofziger, C. Hicks, G. Weinmaster, B.A. Barres. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron. 1998;21:63-75 10.1016/S0896-6273(00)80515-2
- Waxman, 2006 S.G. Waxman. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat. Rev. Neurosci.. 2006;7:932-941 10.1038/nrn2023
- Wegner et al., 2006 C. Wegner, M.M. Esiri, S.A Chance, J. Palace, P. Matthews. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology. 2006;67:960-967 10.1212/01.wnl.0000237551.26858.39
- Wilkins et al., 2001 A. Wilkins, S. Chandran, A. Compston, K.E.Y. Words. in: A Role for Oligodendrocyte-derived IGF-1 in Trophic Support. vol. 57 (, 2001) 48-57 10.1002/glia.1094
- Wilkins and Compston, 2005 A. Wilkins, A. Compston. Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathways. J. Neurochem.. 2005;92:1487-1496 10.1111/j.1471-4159.2004.02981.x
- Williams et al., 2007 A. Williams, G. Piaton, M.S. Aigrot, A. Belhadi, M. Théaudin, F. Petermann, J.L. Thomas, B. Zalc, C. Lubetzki. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis?. Brain. 2007;130:2554-2565 10.1093/brain/awm202
- Williamson and Cleveland, 1999 T.L. Williamson, D.W. Cleveland. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci.. 1999;2:50-56 10.1038/4553
- Witte et al., 2009 M.E. Witte, L. Bø, R.J. Rodenburg, J.A. Belien, R. Musters, T. Hazes, L.T. Wintjes, J.A. Smeitink, J.J.G. Geurts, H.E. De Vries, P. Van Der Valk. Enhanced Number and Activity of Mitochondria in Multiple Sclerosis Lesions. (, 2009) 10.1002/path
- Witte et al., 2010 M.E. Witte, J.J.G. Geurts, H.E. de Vries, P. van der Valk, J. van Horssen. Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration?. Mitochondrion. 2010;10:411-418 10.1016/j.mito.2010.05.014
- Witte et al., 2014 M.E. Witte, D.J. Mahad, H. Lassmann, J. van Horssen. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol. Med.. 2014;20:179-187 10.1016/j.molmed.2013.11.007
- Wolswijk, 1998 G. Wolswijk. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci.. 1998;18:601-609
- Wolswijk and Balesar, 2003 G. Wolswijk, R. Balesar. Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain. 2003;126:1638-1649 10.1093/brain/awg151
- Wood et al., 2012 E.T. Wood, I. Ronen, a. Techawiboonwong, C.K. Jones, P.B. Barker, P. Calabresi, D. Harrison, D.S. Reich. Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J. Neurosci.. 2012;32:6665-6669 10.1523/jneurosci.0044-12.2012
- Wu and Raine, 1992 E. Wu, C.S. Raine. Multiple sclerosis interactions between oligodendrocytes and hypertrophic astrocytes and their occurence in other, nondemyelinating conditions. Lab. Investig.. 1992;67:88
- Wujek et al., 2002 J.R. Wujek, C. Bjartmar, E. Richer, R.M. Ransohoff, M. Yu, V.K. Tuohy, B.D. Trapp. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J. Neuropathol. Exp. Neurol.. 2002;61:23-32
- Xie et al., 2014 C. Xie, Z. Li, G.X. Zhang, Y. Guan. Wnt signaling in remyelination in multiple sclerosis: friend or foe?. Mol. Neurobiol.. 2014;49:1117-1125 10.1007/s12035-013-8584-6
- Ye et al., 2009 F. Ye, Y. Chen, T. Hoang, R.L. Montgomery, X. Zhao, H. Bu, T. Hu, M.M. Taketo, J.H. van Es, H. Clevers, J. Hsieh, R. Bassel-Duby, E.N. Olson, Q.R. Lu. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat. Neurosci.. 2009;12:829-838 10.1038/nn.2333
- Yin and Hu, 2014 W. Yin, B. Hu. Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish. Exp. Neurol.. 2014;251:72-83 10.1016/j.expneurol.2013.11.012
- Yuen et al., 2013 T.J. Yuen, K.R. Johnson, V.E. Miron, C. Zhao, J. Quandt, M.C. Harrisingh, M. Swire, A. Williams, H.F. McFarland, R.J.M. Franklin, C. Ffrench-Constant. Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain. 2013;136:1035-1047 10.1093/brain/awt024
- Zambonin et al., 2011 J.L. Zambonin, C. Zhao, N. Ohno, G.R. Campbell, S. Engeham, I. Ziabreva, N. Schwarz, S.E. Lee, J.M. Frischer, D.M. Turnbull, B.D. Trapp, H. Lassmann, R.J.M. Franklin, D.J. Mahad. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain. 2011;134:1901-1913 10.1093/brain/awr110
- Zhang et al., 2009 Y. Zhang, A.T. Argaw, B.T. Gurfein, A. Zameer, B.J. Snyder, C. Ge, Q.R. Lu, D.H. Rowitch, C.S. Raine, C.F. Brosnan, G.R. John. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc. Natl. Acad. Sci. U. S. A.. 2009;106:19162-19167 10.1073/pnas.0902834106
- Zhang et al., 2014 Y. Zhang, K. Chen, S.A. Sloan, M.L. Bennett, A.R. Scholze, S.O. Keeffe, H.P. Phatnani, P. Guarnieri, C. Caneda, N. Ruderisch, S. Deng, S.A. Liddelow, C. Zhang, R. Daneman, T. Maniatis, B.A. Barres, J.Q. Wu. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci.. 2014;34:1-19 10.1523/jneurosci.1860-14.2014
- Zhang et al., 2015 Y. Zhang, Y. Ping, B. Pepinsky, G. Huang, L.B.E. Shields, C.B. Shields, S. Mi. Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination. Exp. Neurol.. 2015;266:68-73
© 2015 Elsevier Ltd, All rights reserved.