From demyelination to remyelination: the road toward therapies for spinal cord injury.

REVIEW ARTICLE

From Demyelination to Remyelination: The Road Toward Therapies for Spinal Cord Injury Florentia Papastefanaki and Rebecca Matsas Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation. GLIA 2015;63:1101–1125

Key words: oligodendrocytes, nodes of Ranvier, inflammation, glial scar, cell transplantation

Introduction Myelin as an Active Target of Evolution yelin wrapping around neuronal axons—by oligodendrocytes (OLs) in the central nervous system (CNS) and by Schwann cells (SCs) in the peripheral nervous system (PNS)—is considered one of the most recent cytoarchitectural acquisitions in vertebrate evolution found in the oldest jawed fish, the placoderms, dated in the Devonian period (Bullock et al., 1984; Nave, 2010; Zalc and Colman, 2000). This adaptation favored the fast processing of complex information that, combined with rapid and synchronic muscle control enhanced survival through efficient predating and prey’s escaping but also facilitated higher-order cognitive functions. The myelin sheath around axons also facilitated the increase of body size during evolution by reducing the time needed for a nerve impulse to travel along projection neurons with

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up to 1-m long axons in large vertebrates allowing long range connections to operate with millisecond precision (Hartline, 2008; Zalc et al., 2008). Many OLs wrap around a single axon to form the myelinating segments that span its full length. The short space (1 lm) exposed between myelinated segments corresponds to a node of Ranvier, where voltagegated Na1 channels (Nav) are concentrated (Fig. 2). The nerve impulse “jumps” from one node of Ranvier to the next one by a process called saltatory conduction, which facilitates rapid nerve communication in an energy-efficient manner (Hartline, 2008). Myelinating glia constantly communicate with axons providing protection and trophic support and are indispensable for axonal survival and integrity (Edgar et al., 2004, 2009; Griffiths et al., 1998; Lappe-Siefke et al., 2003; Nave, 2010; Yin et al., 1998). In mammals, myelination occurs mostly postnatally following innervation (Sowell et al.,

View this article online at wileyonlinelibrary.com. DOI: 10.1002/glia.22809 Published online March 2, 2015 in Wiley Online Library (wileyonlinelibrary.com). Received Dec 15, 2014, Accepted for publication Feb 11, 2015. Address correspondence to Rebecca Matsas, Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, 11521 Athens; Greece. E-mail: [email protected] From the Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens 11521, Greece

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2003). Comparison of the timing of maturation of myelin in the cerebral cortex of humans and nonhuman primates suggests that myelination is a far more prolonged process in humans characterized by a delayed period of maturation that extends beyond late adolescence, alluding to the evolutionary impact of an enriched cultural environment on nervous system development (Miller et al., 2012). In this context, it is interesting to note that mice with human glial chimeric brains exhibited enhanced synaptic plasticity and learning (Han et al., 2013). Such chimeras are extremely valuable in helping us understand the contribution of glial cells, and in particular OLs, not only in physiology but also in a variety of neurological disorders (Windrem et al., 2014). Despite a wealth of knowledge, many aspects of the structural and functional characteristics of myelin are yet to be explored as revealed by recent important studies. High-throughput electron microscopy reconstructions of single axons of mouse cortical pyramidal neurons brought to light novel myelin features. The investigators observed long (up to 55 mm) unmyelinated stretches along individual axons interspersed with myelinated segments that were most prominent in the superficial cortical layers (Tomassy et al., 2014). The functional significance of these unusually long “nodes” and their potential to permit more complex forms of network integration remain to be seen. Another study consolidated the concept that not only myelin influences electrical activity and neural circuit function but, vice versa, that neuronal activity itself modulates myelination (Gibson et al., 2014). This had been previously shown in vitro and in vivo (Barres and Raff, 1993; Demerens et al., 1996; Gary et al., 2012; Stevens, 2002; Wake et al., 2011) and now for the first time in adult awake mice by optogenetic stimulation [(Gibson et al., 2014) and commented by Bechler and ffrench-Constant (2014)]. It was thus revealed that stimulation of cortical layer V projection neurons resulted in significant oligodendrogenesis and increased myelination suggesting that myelin is an adaptive structure that changes in response to neuronal activity. In support, it has been shown that social behavior and associated neuronal activity regulate myelination in the prefrontal cortex. Adult mice under prolonged social deprivation exhibited impaired myelination in the prefrontal cortex and changes in OL heterochromatin (Liu et al., 2012a). Similarly, young mice isolated for a critical period of 2 weeks immediately after weaning displayed non-reversible alterations in prefrontal cortex function and myelination associated with defective neuregulin-1/ErbB3 signaling (Makinodan et al., 2012). Both these studies provide evidence that social experience and associated neuronal activity, in particular during the juvenile period, is essential for proper myelin formation and normal cognitive function. The concept that myelin is an adaptive structure contributing to CNS plasticity has important 1102

implications for understanding how neuronal circuits work in the healthy and the diseased or injured CNS and may open new avenues for rehabilitation. The existence of a positive feedback loop between neuronal activity and myelinating cells that, if enhanced, could restore function adds value to the significance of training and electrical stimulation toward recovery (Gad et al., 2014). Disruption of Myelin Following Spinal Cord Injury and the Importance of Remyelination for CNS Regeneration After traumatic spinal cord injury (SCI), the elegant formation of myelin and the communication between myelinating glia and axons is disrupted, eventually leading to axonal demyelination and concurrent loss of function. In humans, most injuries are the result of a severe mechanical impact to the spinal cord which causes the primary damage while secondary damage occurs within the next few hours to days (acute phase) and extends over the following weeks (subacute phase), months and years (chronic phase) (Fig. 1). A cascade of deleterious events spreads damage from the original site of injury to the adjacent tissue and establishes a non-permissive to regeneration environment that results in irreversible loss of function (Fitch and Silver, 2008; Silver and Miller, 2004; Thuret et al., 2006). Remyelination is an important feature of the spontaneous regeneration process described in several animal models of SCI and other demyelinating diseases. It refers to the generation of new myelinating cells by resident stem/precursor cells to replace the lost OL and the production of new myelin sheaths around denuded, spared, or regenerated axons (Franklin and Ffrench-Constant, 2008; Franklin and Gallo, 2014). The importance of remyelination is dual: first, there is evidence that impulse conduction can be restored by the formation and proper reconstruction of nodal and internodal regions on the remyelinated axons (Akiyama et al., 2002; Black et al., 2006; Felts and Smith, 1992; Honmou et al., 1996); second, axonal vulnerability to cues of the noxious tissue environment can be avoided by the protection and metabolic support conferred by OLs and myelin to spared or regenerated axons (Duncan et al., 2009; Edgar and Nave, 2009; Funfschilling et al., 2012; Irvine and Blakemore, 2008; Lee et al., 2012b). Nevertheless, spontaneous remyelination is inadequate and does not lead to functional recovery. Therefore a key issue that has to be addressed is how to prevent demyelination at early stages and how to boost remyelination at later stages of SCI. According to studies in humans and rodents, demyelination of spared axons occurs in the regions surrounding the injury during the acute and subacute phases after SCI (Guest et al., 2005; Totoiu and Keirstead, 2005). Still there is Volume 63, No. 7

Papastefanaki and Matsas: Myelin Repair in Spinal Cord Injury

FIGURE 1: The time-line of histological, cellular and molecular events that take place at each of the progression stages during primary and secondary damage after SCI. Primary damage causes disturbances in the myelin sheath without necessarily affecting spared axons at this stage. During the next few hours microglia—the resident immune cells of the CNS—are activated and together with infiltrating peripheral leucocytes cause inflammation (David and Kroner, 2011; Zhou et al., 2014). Additional pathological events in the acute and subacute phases of secondary injury include the formation of edema, ischemia, excitotoxicity, oxidative stress, and accumulation of free radicals that altogether lead to OL cell death, further myelin sheath disassembly and breakdown, impairment of saltatory conduction, and axonal damage (Hagg and Oudega, 2006; Oyinbo, 2011). Additionally, astrocytes become activated and contribute to the formation of the glial scar which is consolidated during the chronic phase of injury.

controversy as to whether it persists in the chronic stages of SCI and whether it is an important contributor to functional impairment (Kakulas, 1999; Lasiene et al., 2008; Salazar et al., 2010). James et al. (2011) demonstrated that acutely after injury in adult rats (during the first week) there is complete conduction block in ascending dorsal column axons, while during the subacute phase (2–4 weeks) the conduction is partially restored with no further improvement at the chronic phase (3–6 months) (James et al., 2011). Moreover, these authors identified a population of chronically demyelinated axons that remain intact but are unable to conduct electrical activity. These axons represent a prime target for remyelination strategies. In this review, we will discuss recent findings on the pathophysiology of myelin after SCI that provide prospects for the design of efficient therapies based on newly identified targets. We mainly focus on recent data gathered from studies on SCI for which well-established animal models exist, but we also discuss evidence from other relevant animal models of demyelination pertinent to human neurological disease such as multiple sclerosis (MS), as recent work has revealed a variety of targets that may prove beneficial for SCI.

Disorganization of the Architecture of Myelinated Fibers and Conduction Block: Can Functionality Be Restored? The node of Ranvier and neighboring domains form a region of dynamic cellular and molecular interactions between the July 2015

axon and the myelinating glial cell that is periodically repeated along a myelinated fiber (Fig. 2). Disturbance of the architecture at the nodes of Ranvier causes delayed or blocked conduction and function loss before any signs of myelin removal or degradation (Fig. 2). Understanding how the nodal molecular and cellular architecture is affected upon injury is of great importance for the design of relevant therapeutic approaches that would hinder or neutralize the dysfunctional phenotype. Early after SCI, the juxtaparanodal region is disrupted and voltage gated potassium channel (Kv) subunits become markedly dispersed along the injured axons (Fig. 2) (Karimi-Abdolrezaee et al., 2004; Ouyang et al., 2010). As a consequence, induced outward potassium currents inhibit the generation of an action potential while administration of the Kv channel blocker 4-aminopyridine (4AP) after injury immediately restores axonal excitability (Ouyang et al., 2010). Disarrangement of the nodal architecture also results in diffuse localization of the Nav channels outside the nodes of Ranvier, contributing to reduced conduction velocity (Craner et al., 2004b; Hunanyan et al., 2011). Structural and biochemical alterations at the nodes of Ranvier, independent of overt demyelination, were also observed in a transgenic mouse model of conditional OL ablation (Oluich et al., 2012). Selective depletion of OLs in this model resulted in severe clinical dysfunction with ascending spastic paralysis ultimately causing fatal respiratory impairment. Surprisingly, the severe pathology was not

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FIGURE 2: Diagram of the architecture of the CNS myelinated fibers at the nodes of Ranvier in the intact (top) and acutely injured (bottom) spinal cord. Top: The node of Ranvier, where Nav are clustered is flanked by the paranodes where the axonal membrane is in contact with loops of non-compact myelin, the paranodal loops. These domains act as lateral diffusion barriers for the molecules anchored at the nodes, through axon–glia membrane interactions (Charles et al., 2002; Labasque and Faivre-Sarrailh, 2010; Sherman et al., 2005; Susuki and Rasband, 2008). Upon membrane depolarization, concentrated Nav channels allow rapid influx of Na1 ions triggering a wave of electrical activity. The high resistance and low capacitance of myelin prevents diffusion of the ion current guiding it to the next node of Ranvier. Juxtaparanodes separate paranodes and internodes and are the regions under the compact myelin wrap, where the Shakertype voltage gated potassium (Kv) channels that participate in stabilizing the axonal membrane potential, are clustered (Poliak and Peles, 2003; Vabnick et al., 1999). Bottom: Early after injury the nodal architecture is disrupted, sodium and potassium channels lose their confinement to distinct territories and acquire a more diffuse distribution along the axon which leads to impairment or block of saltatory conduction.

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accompanied by widespread myelin degradation. Instead, it was the changes and loss of key symbiotic interactions between OLs and the axons that produced the profound functional consequences observed. The above findings indicate that the functional deficit due to conduction block is initially attributed to disturbance of the myelin sheath in the absence of myelin degradation. The consequence is an alteration in the distribution of sodium and potassium channels that affects conductivity. Lateral diffusion of Nav (Craner et al., 2004a) and Kv channels (Zoupi et al., 2013) also occurs in models of CNS demyelination such as experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. Based on these observations, therapeutic approaches toward eliminating conduction block and protecting axons from vulnerability include pharmacological regulation of Kv channel activation and protection of OLs from death at the early phases after SCI. 4-AP has already been marketed for the treatment of MS and data from SCI patients in clinical trials were encouraging but the narrow effective range that is close to the safety dosage and serious side effects hold back 4-AP from clinical application for SCI [for review see (Shi and Sun, 2011)]. Four different analogs of 4-AP have been developed and proven capable of enhancing axonal conduction in ex vivo models of SCI (McBride et al., 2006, 2007; Smith et al., 2005; Sun et al., 2009, 2010) with 4-aminopyridine-3-methanol (4-AP-3MeOH) showing the best efficacy due to its lower effective concentration and therefore limited dose-related side-effects (Sun et al., 2009, 2010).

Oligodendrocyte and Myelin Loss: How to Protect and Prevent During the acute and subacute phases of secondary injury, several cellular and molecular events result in OL death eventually causing myelin loss. Among these events, haemorrhage, ischemia, free radical production, immune cell activation and infiltration, dysregulation of ion equilibrium, and excitotoxicity lead to OL necrosis or apoptosis (Fig. 1) (Oyinbo, 2011). Prevention of myelin degradation and/or clearance of myelin debris is critical not only for axonal regeneration (Filbin, 2003) but also for the differentiation of oligodendrocyte progenitor cells (OPCs) into mature OLs during remyelination (Kotter et al., 2006). Rescuing one OL could potentially protect many axons given that a single OL myelinates multiple axons (Crowe et al., 1997; Grossman et al., 2001; Lytle and Wrathall, 2007). Since by Day 1 after SCI, the OL population is already reduced to half in and around the injury site, it is important to halt the self-propelling mechanism of secondary damage as early as possible. Considering that the intervention time window is limited to the first 24 h, immediate administration of a ready-to-use drug with extended July 2015

half-life could be of significant clinical value. Given the complex hardware of spinal interneuronal networks and their crosstalk with corticospinal motor neurons (Miri et al., 2013), it is vital to protect the network from damage before trying to rebuilt it. Early spinal decompression and stabilization surgery within 24 h after injury is gaining ground as an effective treatment for minimizing neurological damage in SCI patients that are not in a life-threatening situation and without medical co-morbidities (Fehlings et al., 2012), providing at the same time opportunities for local delivery of early-phase drugs such as those discussed below. Polyethylene Glycol Protects by Sealing the Disrupted Cell Membranes An interesting approach to minimize detrimental effects of secondary injury is to protect the membrane integrity of injured cells at the early phases after SCI. Polyethylene glycol (PEG) is a recognized membrane sealant that has been administered in CNS injury models promoting restoration of function by decreasing membrane permeability, silencing oxidative stress, and diminishing neuroinflammation (Fig. 3) (Baptiste et al., 2009; Luo et al., 2002, 2004; Luo and Shi, 2004). Yet, there are limitations to clinically adapting PEG administration mostly emerging from its toxicity and limited bioavailability when given systemically or locally (Cho and Borgens, 2012; Cole and Shi, 2005). Therefore recent attempts have focused on optimizing PEG pharmacokinetics by linking it to nanoparticles, such as silica or other nanoscale copolymer micelles (Chen et al., 2012; Cho et al., 2008, 2010; Shi et al., 2010). Recently, we have used gold nanoparticles functionalized with PEG in a mouse model of compression SCI. Gold nanoparticles appear as leading candidates in the field of nanomedicine, due to their inert and nonimmunogenic characteristics, good biocompatibility and biodistribution, ease of preparation, and modification. Their potential as a versatile platform for drug delivery has been demonstrated in various studies, including targeting of cancer cells (Dreaden et al., 2012). However, less attention has been paid to neurological disorders or neurotrauma. Intraspinal delivery of PEG-functionalized 40-nm-gold nanoparticles at early stages after mouse SCI promoted locomotor recovery and was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons (Papastefanaki and Matsas, unpublished observations). These results suggest that PEG-functionalized gold nanoparticles improve behavioral recovery after SCI by minimizing the acute phase of damage thus allowing for regeneration and remyelination. The potential of this nanocarrier system as a drug delivery vehicle for acute interventions after SCI is appealing as its intrinsic beneficial properties could be combined with biomolecular 1105

FIGURE 3: Cellular and molecular events related to oligodendrocyte loss at the acute and subacute phases of SCI that present potential targets for oligodendrocyte protection and efficient therapeutic treatment with small molecules and biomaterials.

enhancers of regeneration. Such an approach may also be effective for clinical adaptation not only during the acute, but also the subacute or chronic phases of injury, especially in the light of the significant long-lasting functional improvement observed in chronic severe SCI following scar resection and PEG-matrix implantation (Estrada et al., 2014) or the administration of single-walled carbon nanotubes functionalized with PEG (Roman et al., 2011). Can Oligodendrocytes Be Protected from Excitotoxicity and Oxidative Stress? The levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are dramatically elevated during the acute phase of SCI, leading to toxic oxidation of the major 1106

components of myelin, lipids, and proteins, eventually resulting in OL death (Dewar et al., 2003). Certain features render OLs particularly vulnerable to oxidative stress. First, they operate under a high metabolic rate—far greater than any other cell type in the brain—essential for myelin synthesis and maintenance (Connor and Menzies, 1996). Second, OLs contain high levels of iron as many enzymes participating in myelin synthesis and metabolism require iron as a co-factor (Schulz et al., 2011; Thorburne and Juurlink, 1996). Third, OLs have low levels of glutathione, a robust antioxidant. Consequently, OLs are at greater risk of damage should oxidative signals and/or intracellular iron increase. Because of this particular metabolic profile, also shared by OPCs, understanding the underlying mechanisms and designing Volume 63, No. 7


appropriate therapeutic approaches that aim at scavenging, silencing, or neutralizing the effect of the mediators of oxidative stress represents a challenging task (Hall, 2011; Jia et al., 2012). Since OLs lack the appropriate antioxidant defense mechanisms, their fate in the presence of free radicals largely depends on antioxidant support from other cells, such as astrocytes, which clear excess extracellular glutamate by reuptake. However, upon injury this mechanism is disrupted and astrocytes directly induce glutamate excitotoxicity and subsequent oxidative stress in OLs through activation of the astroglial nuclear factor-jB (NF-jB) transcription factor (Johnstone et al., 2013a). Clearance of glutamate by astrocytes is blocked by pro-inflammatory cytokines at the site of injury, such as tumor necrosis factor (TNF) and interleukin1b (IL-1b) (Chao et al., 1995; Pitt et al., 2003; Takahashi et al., 2003) as well as by ROS (Piani et al., 1993; Volterra et al., 1994). This phenomenon can be reversed by IL-10 treatment which decreases the levels of these proinflammatory cytokines and reactive species (Fig. 3) (Genovese et al., 2006, 2009; Plunkett et al., 2001). Notably, prevention of NF-jB activation in astrocytes after SCI reduces OL cell death (Johnstone et al., 2013a), enhances oligodendrogenesis (Bracchi-Ricard et al., 2013) and results in significantly improved motor performance (Brambilla et al., 2005, 2009). OLs express AMPA (a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid), kainite, and NMDA (N-methyl-Daspartate) receptors that render them susceptible to damage by excessive glutamate signaling both in vitro and in vivo (Follett et al., 2000; Matute, 1998; Matute et al., 1997; Sanchez-Gomez et al., 2011). Excess glutamate causes prolonged activation of glutamate receptors, which results in dangerously high levels of intracellular Ca21. Elevated Ca21, in turn, initiates several destructive cascades causing mitochondrial disruption, ROS production, and cytochrome c release (Deng et al., 2006; Matute et al., 2002). A contributing factor is that OLs and their progenitors express a form of AMPA receptors lacking a particular subunit (GluR2) which increases the channel permeability for Ca21 (Tanaka et al., 2000). These collective events orchestrate necrotic and apoptotic OL death. Interestingly, ionotropic receptor antagonists have been shown to ameliorate neurological deficits in animal models of cerebral ischemia and multiple sclerosis (Pitt et al., 2000; Salter and Fern, 2005; Tekkok and Goldberg, 2001). Moreover, a combinatorial treatment of the injured spinal cord consisting of blocking Na1/Ca21-permeable AMPA receptors with NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f ]quinoxaline-2,3-dione), together with inhibiting NADPH (nicotinamide adenine dinucleotide phosphate) oxidase with apocynin [NADPH oxidase inhibitor (Stefanska July 2015

and Pawliczak, 2008)] resulted in superior motor function recovery that was related to reduced white matter damage and serotoninergic fiber sparing (Fig. 3) (Johnstone et al., 2013b). Topiramate, another AMPA specific glutamate receptor antagonist [approved by US Food and Drug Administration (FDA)] when delivered intraspinally 15 min after SCI in a rat model, protected both OLs and motor neurons more efficiently than NBQX (Gensel et al., 2012), suggesting that if used in combination with apocynin its beneficial effects might be further enhanced (Fig. 3). Zinc homeostasis is also critical for OL vulnerability to excitotoxicity and oxidative stress. Activation of OL AMPA receptors has been shown to trigger rapid elevation of cytosolic Zn21 and its accumulation contributes to mitochondrial dysfunction, ROS production, and thus AMPA receptor-mediated excitotoxicity (Mato et al., 2013). Methylprednisolone Revisited Methylprednisolone (MP) is a synthetic glucocorticoid agonist with potent anti-inflammatory and anti-oxidant properties that has been used systemically for clinical therapy of a variety of neurological disorders involving white matter injury, such as multiple sclerosis and SCI. A major drawback, especially for SCI patients, is the high-dose regimen required (Hall and Springer, 2004). Even though controversy stands for about 20 years regarding its marginal efficacy vis-a-vis its side-effects, MP treatment remains the only approved therapy applied in SCI patients. The mechanism of MP action is largely unspecified. Administration of a single dose of MP as early as 10 min after SCI in rats resulted in a significant decrease of apoptotic cells (Vaquero et al., 2006). Unexpectedly, it was demonstrated that MP has a selective action on OLs: upon AMPA treatment in vitro and after SCI in vivo MP attenuated OL death while neurons were not rescued (Lee et al., 2008; Xu et al., 2009). The molecular cascade involves binding of MP to the cytoplasmic glucocorticoid receptor (GR), dimerization of GR and translocation to the nucleus, interaction with the transcription factor STAT5 (signal transducer and activator of transcription 5), and upregulation of the expression of the prosurvival protein bcl-XL (Fig. 3) (Xu et al., 2009). Whether activation of GR leads in up-regulation or down-regulation of bcl-XL to respectively exert an anti-apoptotic or pro-apoptotic role, is modulated in a cell-dependent context and probably this explains the antiapoptotic effect of MP only on OLs but not on neurons (Xu et al., 2009). MP treatment also attenuates astroglial activation and the production of chondroitin sulfate proteoglycans (CSPGs) which are associated with inhibition of neurite outgrowth, remyelination, and axonal regeneration (Liu et al., 2008). Together with the anti-inflammatory and antioxidant properties initially attributed to MP (Hall and Springer, 1107

2004), these new findings provide stronger credentials to MP treatment. An interesting approach to circumvent the unwanted consequences of systemic corticosteroid therapy and maximize its therapeutic efficacy (Gerndt et al., 1997; Qian et al., 2005) involved loading of MP on biodegradable poly(lactic-co-glycolic acid)-based nanoparticles which were delivered intraspinally into the injured rat spinal cord with or without hydrogel embedding (Chvatal et al., 2008; Kim et al., 2009). In this way, a localized and sustained release of MP was achieved that resulted in improved functional recovery relative to systemic MP delivery (Kim et al., 2009). Interfering with Endoplasmic Reticulum Stress and the Unfolded Protein Response in Oligodendrocytes Upon SCI, the function of the endoplasmic reticulum (ER) is perturbed and cells activate an integrated signaling response termed the unfolded protein response (UPR), which aims to re-establish homeostasis (Gotoh and Mori, 2006; Hetz, 2012; Kaufman, 1999; Matus et al., 2011; Park et al., 2004; Tarabal et al., 2005). During ER stress, unfolded or misfolded proteins accumulate in the ER lumen and the UPR aims to restore normal function by halting protein translation and degrading misfolded proteins (Fig. 3) (Hetz, 2012). In chronic ER stress, the UPR is not sufficient to restore homeostasis and the cells are driven to apoptosis (Woehlbier and Hetz, 2011). Several markers of ER stress have been found up-regulated in SCI and ischemia (Aufenberg et al., 2005; Paschen et al., 2003; Penas et al., 2007, 2011; Yamauchi et al., 2007) and recently it was shown that a UPR response related to the transcription factors X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) is rapidly triggered within the first 3 h after SCI (Valenzuela et al., 2012). In support, knocking down each of the two transcription factors in mice resulted in significant impairment of locomotor recovery as compared with wild-type mice. The ATF4-deficient mice exhibited reduced activation of microglia and higher levels of pro-inflammatory cytokines (IL-1b, TNFa, and IL-6), reduced numbers of OLs and enhanced axonal degeneration, presumably as a result of OL dysfunction (Valenzuela et al., 2012). In contrast, overexpression of XBP1 locally into the spinal cord ameliorated the fine locomotor movements and increased the number of oligodendroglia in the injured tissue, despite the already activated endogenous pathway (Valenzuela et al., 2012). Moreover, when the pro-apoptotic factor CHOP (CCAAT-enhancerbinding protein homologous protein) was absent in mild but not severe SCI mice, motor recovery was enhanced with concurrent protection of OLs and white-matter sparing. CHOP is a downstream effector of the UPR that controls late-phase genes related to apoptosis and upon injury it is up-regulated 1108

in neurons and OLs but not in astrocytes, indicating the differential vulnerability of the different cell types to ER stress (Hetz et al., 2011; Ohri et al., 2011, 2012). Based on these data, attenuation of the ER stress with concomitant upregulation of the UPR or inhibition of its pro-apoptotic downstream effectors by using small molecules might be beneficial for protecting early tissue damage and enhancing functional recovery. During ER stress, phosphorylation of the elongation initiation factor 2a (eIF2a) by PERK (PKR-like endoplasmic reticulum eIF2alpha kinase) inhibits translation initiation and global protein synthesis, as a cell protective mechanism. This process is reversed by the protein phosphatase 1 (PP1) complex that de-phosphorylates eIF2a, aggravating cellular injury. Salubrinal, a small molecule inhibitor of the PP1 complex, improved functional recovery of hindlimb locomotion when delivered intravenously acutely after mouse contusion SCI by attenuating OL apoptosis and sparing white matter (Fig. 3) (Ohri et al., 2013). In vitro, salubrinal also protects mouse OPCs against ER stress-induced apoptosis (Ohri et al., 2013) and OLs from AMPA excitotoxicity (Ruiz et al., 2010). Salubrinal is not FDA approved for clinical use, but another small molecule, guanabenz (FDA approved for the treatment of hypertension) with similar activity in enhancing eIF2a signaling by targeting the PP1 complex, was found to protect OPCs from ER stress-mediated cell death in vitro and attenuated the ER stress response in vivo after SCI (Saraswat Ohri et al., 2014). However no locomotor recovery was achieved reflecting the complexity of the mechanisms involved. Inhibiting the RhoA/JNK3 Apoptotic Pathway in Oligodendrocytes Nerve growth factor (NGF) is an important neurotrophin for neuronal survival and differentiation by binding and activating tyrosine kinase receptor A (TrkA) (Levi-Montalcini, 1964, 1987). Yet its precursor, proNGF, induces apoptosis by binding to the p75 neurotrophin receptor (p75NTR)-sortilin complex (Fig. 3). The proteolysis of proNGF, mediated by the enzyme matrix metalloproteinase 7 (MMP-7) and regulated by tissue inhibitor of metalloproteinase 1 (TIMP-1), is probably a critical checkpoint in determining the extent of cell death after injury when the levels of both proNGF and p75NTR are elevated (Beattie et al., 2002; Le and Friedman, 2012; Tep et al., 2013). Two weeks after contusion SCI p75NTR is expressed in OLs, SCs, and in motor neurons while it is not detected in microglia and astrocytes (Tep et al., 2013). In contrast, proNGF is predominantly expressed by microglial cells after SCI and contributes to the death of OLs (Fig. 3) (Yune et al., 2007). Minocycline is a derivative of tetracycline that mediates neuroprotection in experimental models of CNS injury and neurodegenerative diseases (Chen Volume 63, No. 7


et al., 2000; Du et al., 2001; Lee et al., 2003; Yrjanheikki et al., 1998; Zhu et al., 2002). Its neuroprotective role is facilitated by inhibition of microglial activation that results in protecting OLs from apoptosis. This procedure is partly mediated by inhibition of p38 mitogen activated protein kinase (p38MAPK)-dependent proNGF production in activated microglia (Fig. 3) (Yune et al., 2007). In a successful attempt to maximize stability and sustained local release, minocycline has been loaded in nanoparticles composed by a polymer based on poly-e-caprolactone and PEG. These nanoparticles were able to selectively target and specifically modulate the activated pro-inflammatory microglia/macrophages (Papa et al., 2013). A similar protective role for OLs and myelin after SCI was attributed to early (up to 6 h after injury) administration of fluoxetine, a selective serotonin reuptake inhibitor with known anti-depressant action (Yune et al., in press). Treatment with fluoxetine after SCI inhibits microglia activation and p38MAPK-dependent proNGF expression (Fig. 3). In addition, fluoxetine attenuates the activation of Ras homolog gene family member A (RhoA) and decreases the level of phosphorylated c-Jun, ultimately inhibiting caspase-3 activation and significantly reducing cell death of OLs (Yune et al., in press). Yet, care should be taken when modulating inflammation because several studies show that when macrophage activation is repressed, remyelination is inhibited (Kotter et al., 2001; Li et al., 2005; Miron et al., 2013). A more selective intervention to specifically block proNGF action in OLs without attenuating microglial activation would be desirable. LM11A-31 is a non-peptide small molecule that binds to p75NTR and perturbs its interaction with proNGF (Fig. 3) (Massa et al., 2006). When administered orally, starting 4 h after SCI, it effectively crosses the blood– spinal cord barrier and is able to block OL apoptosis, increase the number of myelinated axons, and improve functional recovery without obvious adverse effects (Tep et al., 2013). LM11A-31 administration modulates p75NTR signaling and results in attenuation of the apoptotic downstream effector cJun N-terminal kinase 3 (JNK3) activity thereby hindering release of cytochrome c from mitochondria (Li et al., 2007; Tep et al., 2013). JNK3 activity is up-regulated and sustained for a prolonged period of several days after SCI while apoptotic cell death of OLs is reduced in JNK32/2 mice suggesting that the JNK3 pathway is involved in OL cell death after SCI (Li et al., 2007). Even though oral administration of LM11A-31 seems an effective non-invasive approach, the relatively short half-life (3–4 h) of the molecule is likely to hold down its effect unless a more frequent schedule that twice daily is applied (Tep et al., 2013) or even better if it is loaded on functionalized nanoparticles or other biomaterials to ensure controlled and sustainable local release (Cho and Borgens, 2012; Kubinova and Sykova, 2010; Perale et al., 2012; Rossi et al., 2013). July 2015

JNK3 acts downstream of RhoA following p75NTR activation and therefore RhoA is another potential therapeutic target for SCI (Fig. 3) (Dubreuil et al., 2003; McKerracher and Higuchi, 2006; Yune et al., 2007). Following axonal injury in SCI rodents, RhoA is highly up-regulated and substantially activated in different types of cells including OLs (Conrad et al., 2005; Dubreuil et al., 2003). RhoA inactivation by the selective inhibitor C3 transferase has been shown to efficiently protect OLs from death (Dubreuil et al., 2003). BA-210, a recombinant variant of C3 transferase is a drug trademarked as Cethrin which blocks Rho activation and has proven effective for the treatment of SCI in pre-clinical studies by reversing the effect of extracellular inhibitory substrates on neurons and promoting regeneration (Lord-Fontaine et al., 2008). Compared with C3 transferase, Cethrin can easily cross the dura of the spinal cord as well as the cell membrane via a receptor-independent mechanism. Cethrin was tested for safety and efficacy in a phase I/IIa clinical trial in patients with acute complete [American Spinal Injury Association impairment scale (ASIA) A] cervical or thoracic SCI. The drug was applied through a fibrin-mediated delivery system onto the dura matter at the lesion site of patients scheduled for decompression or fixation surgery during the first week after injury. All doses were safe and well-tolerated and no severe adverse effects were attributed to the drug. ASIA assessment, in the 1-year follow-up, showed important improvement above basal predicted levels, mainly in the cervical patients (Fehlings et al., 2011; McKerracher and Anderson, 2013). The RhoA-JNK3 pathway in OLs is also target for the ovarian steroid hormone 17b-estradiol (Fig. 3) (Harrington et al., 2002; Jurewicz et al., 2003; Lee et al., 2012a) and for the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and indomethacin that reduce apoptotic cell death of OLs upon administration in SCI models (Fig. 3) (Xing et al., 2011). Hence RhoA signaling is indeed an important therapeutic target for promoting recovery of the injured CNS.

Spontaneous Remyelination Occurs After SCI but is Inadequate for Repair Despite novel findings that hold promise for efficient protection of OLs and myelin early after SCI, interventions targeting chronic demyelination remain a challenging task. Spontaneous remyelination takes place but unfortunately is highly insufficient as it fails to regenerate the lost myelin. Nevertheless, boosting the endogenously activated process by external factors could prove to be a therapeutically relevant strategy. Post-mitotic OLs do not participate in remyelination (Crang et al., 1998; Keirstead and Blakemore, 1997). Resident glial progenitors (OPCs), expressing platelet derived 1109

FIGURE 4: Spontaneous remyelination occurs after SCI but is inadequate for repair. Several approaches applicable at the subacute and/ or chronic phases of SCI could potentially boost remyelination toward functional restoration.

growth factor receptor a (PDGFRa) and NG2, proliferate in response to injury and migrate to the lesioned area within the first week while during the following weeks to months they differentiate into mature myelinating OLs (Fig. 4) (Nishiyama, 1998; Powers et al., 2013; Zawadzka et al., 2010). A fraction of myelinating OLs derives from ependymal cells (Fig. 4) of the central canal which possess neural stem cell properties (Barnabe-Heider et al., 2010; Lacroix et al., 2014). These cells are activated after SCI and produce not only scarforming glial cells but also OLs even though at a lesser degree (Meletis et al., 2008). SCs which constitute the myelinating cells of the PNS also contribute to CNS remyelination (Fig. 4). SCs infiltrate the injured spinal cord presumably through dorsal root entry zones, but are also generated in the CNS from OPCs (Jasmin et al., 2000; McTigue et al., 2006; Stegmuller et al., 2002; Zawadzka et al., 2010). As shown by genetic fate-mapping, at least half of the cells generated from PDGFRa-expressing OPCs are SCs, indicating that they are not a minor byproduct in OPC differentiation during remyelination (Zawadzka et al., 2010). The implications of SC remyelination of CNS axons are not well-understood. Since SCs

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remyelinate axons larger than 1-lm in diameter, it may be that the participation of SCs to CNS remyelination serves as a fast response for quick restoration of saltatory conduction and neuroprotection of large axons (Powers et al., 2013). However, further work is needed to clarify from a functional point of view the effects of SC-derived versus OL-derived remyelination. As evidenced in post-mortem tissue of MS patients and in mouse models of MS, the regenerating myelin sheath is abnormally thinner and shorter. Despite this, remyelination is sufficient to restore saltatory conduction and support axonal integrity, ensuring functional recovery of the axon (Fancy et al., 2011; Guest et al., 2005; Irvine and Blakemore, 2008; Nashmi and Fehlings, 2001; Nave, 2010; Smith et al., 1979). Recently, Powers et al. (2013) questioned the current view that newly formed myelin possesses abnormal morphological features. Using a Cre-inducible transgenic mouse model with targeted Cre-expression in a subset of glial progenitor cells after SCI, these authors achieved remarkably clear visualization of spontaneously regenerated myelin in vivo. They found that although early after injury, the mean length of sheaths regenerated by SCs and OLs was significantly shorter than in

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uninjured myelin, by 6 months post-injury the newly formed myelin sheaths were neither thinner nor shorter than control myelin. Notably, myelin internodes started forming by the second week after injury and elongated independently of axonal growth, in contrast to myelination during development while they eventually reached lengths and thicknesses within the normal range (Powers et al., 2013). Several signaling pathways have been implicated in CNS remyelination. For example, the ERK1/2 MAPK signaling pathway serves as a rheostat for controlling myelin thickness (Fyffe-Maricich et al., 2013). Increased expression of phosphorylated Erk1/2, specifically in cells of the OL lineage, is sufficient for accelerated generation of thicker myelin sheaths surrounding remyelinated axons (Fyffe-Maricich et al., 2013). Specific growth factors participate in OPC recruitment and differentiation mechanisms. PDGF is involved in the initial phase of OPC recruitment while insulin-like growth factor I (IGF-I) and transforming growth factor b1 (TGF-b1) trigger the differentiation of the recruited cells into myelinating OLs. The levels of these factors are reduced during aging likely due to differences in the macrophage response in young and old animals (Hinks and Franklin, 2000). Indeed, the degree of demyelination and the rate of remyelination as well as functional recovery are declining with age, presenting a serious obstacle to therapy, particularly for patients subject to long-term demyelinating diseases such as MS and for the ageing population of the western world that is susceptible to SCI (Siegenthaler et al., 2008). The decline in remyelination has been attributed to an age-dependent epigenetic control of gene expression (Shen et al., 2008). In demyelinated young brains, new myelin synthesis is preceded by recruitment of histone deacetylases (HDACs) to promoter regions of OL differentiation inhibitors, such as Hes5, and genes associated with neural stem cell self-renewal, such as Sox2. In demyelinated old brains, HDAC recruitment is inefficient, and this allows the accumulation of transcriptional inhibitors preventing myelin gene expression. Interestingly, heterochronic parabiosis experiments demonstrated that remyelination is enhanced in old mice exposed to a young systemic environment (Ruckh et al., 2012). Restored remyelination in the old mice required recruitment of blood-derived monocytes from the young animals, suggesting that in this respect “young” blood rejuvenates “old” brains. Another problem that interferes with remyelination is that myelin debris contain molecules inhibitory to OPC differentiation, such as Nogo 66, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) (Kotter et al., 2006), which act on OPCs via the NOGO receptor complex and particularly its components TROY (Sun et al., 2014) and LINGO-1 (Mi et al., 2007, 2013). Interfering with these interactions either by genetic means or July 2015

through small molecular inhibitors (Mi et al., 2013; Sun et al., 2014) or even introducing “young” blood-derived macrophages that have a greater capacity for efficient clearance of myelin debris (Ruckh et al., 2012) could aid endogenous remyelination but more pre-clinical data is needed to go forward.

Boosting Endogenous Remyelination Immunomodulation The prospective positive or negative effects of the innate and adaptive immune responses in CNS regeneration after injury or disease have long been the subject of considerable debate. Although there is evidence that activated immune cells contribute to secondary damage in CNS injury and disease, other studies have provided evidence of their protective role under such conditions (Yong and Rivest, 2009). It is therefore becoming apparent that activation of the immune system and the inflammatory response are essential parts of tissue regeneration and remyelination, presenting an opportunity to exploit their favorable properties toward new therapeutic strategies for SCI. Microglia are the resident macrophages of the adult CNS and are on constant patrol for perturbations resulting from injury or disease. Upon injury, microglia respond rapidly to local signals, such as extracellular ATP and NO, and are recruited timely to the site of injury establishing the first potential barrier between healthy and injured tissue (Davalos et al., 2005, 2012; Dibaj et al., 2010; Haynes et al., 2006; Nimmerjahn et al., 2005). Activated microglia are proliferating cells with a characteristic amoeboid morphology that distinguishes them from resting cells. Concurrently, circulating monocytes infiltrate the CNS and differentiate into macrophages. Indistinguishable in terms of morphology and antigenic markers, the two populations are referred to collectively as microglia/macrophages. They phagocytose tissue debris and red blood cells, present antigens to cytotoxic T lymphocytes, and secrete growth factors, cytokines, reactive oxygen and nitrogen species and glutamate that all influence the demyelination/remyelination process [for review see Miron and Franklin (2014)]. Macrophages have been demonstrated to balance between two distinct activation states (Kigerl et al., 2009). Immediately after injury macrophages polarize toward the “classically activated” state, in response to interferon g (IFN-g), and secrete pro-inflammatory cytokines, proteases, and reactive species contributing to secondary injury (Edwards et al., 2006; Miron et al., 2013). The “alternatively activated” M2 cells, which appear later and peak transiently in response to IL-4/IL13 or IL-10, exhibit enhanced phagocytosis, promote angiogenesis, and secrete anti-inflammatory cytokines, growth factors, and neurotrophic factors, important for axonal regrowth and remyelination (Durafourt et al., 1111

2011; Edwards et al., 2006; Miron et al., 2013). Bloodderived pro-inflammatory M1 and anti-inflammatory M2 macrophages home the injured spinal cord through different portals: cells acquiring M1 phenotype enter via the adjacent spinal cord leptomeninges, while cells acquiring M2 phenotype travel through a remote blood/cerebrospinal fluid/brainventricular choroid plexus epithelium, suggesting that the route of monocyte entry to the CNS system provides an instructional environment to shape their function (Shechter et al., 2013). Importantly, blocking the entry of the resolving M2 cells to the contused spinal cord impairs locomotor recovery. M1 cells are maintained at sites of SCI at least for 1 month outnumbering the comparatively smaller and transient M2 macrophage population that lasts for 3–7 days post-injury (Kigerl et al., 2009). The use of the lys-EGFP-ki mouse model in which blood-derived macrophages can be distinguished from microglial macrophages, revealed that blood-derived M1 cells appear acutely within the spinal lesion followed by increasing numbers of blood-derived M2 cells while in the chronic phase the numbers of blood-derived M1 cells increase again and are greater than blood-derived M2 cells (Thawer et al., 2013). The microglial-derived macrophages are always more numerous than the blood-derived macrophages (Thawer et al., 2013) and play a major role in the early response to SCI by phagocytosing damaged or degenerating tissue while they remain viable for a long time. In contrast, blood-derived macrophages are less efficient in processing CNS debris and die early (Greenhalgh and David, 2014). Orchestration and fine tuning of the M1/M2 ratio present opportunities for efficient remyelination after SCI. Indeed, both populations may be important, with M1 macrophages contributing to OPC recruitment and proliferation at early stages and M2 driving OPC differentiation at later stages via secretion of activin-A, a member of the TGF-b superfamily (Miron et al., 2013). Again ageing is an impeding factor delaying M2 polarization and the related OPC differentiation (Miron et al., 2013). Although phagocytosis of myelin in vitro promotes M2 polarization, macrophages in the injured spinal cord retain a predominantly M1 state that is detrimental to recovery (Boven et al., 2006; Kroner et al., 2014; Liu et al., 2006). Two factors have been identified that synergize toward M1 polarization in the injured CNS. First, TNF prevents phagocytosis-mediated shift toward M2 cells in vitro and in vivo after SCI. Second, iron that accumulates in macrophages after SCI due to phagocytosis of red blood cells and local tissue increases TNF expression and induces a rapid switch of the balance that favors predominant and prolonged M1 macrophage polarization, detrimental to recovery after SCI (Boven et al., 2006; Kroner et al., 2014; Liu et al., 2006). 1112

When considering the adaptive immune response, an even more complex and dynamic immune cell network activated upon CNS injury is highlighted, potentially presenting more opportunities for therapeutic interventions. In a recent study, the authors addressed the cross-talk between effector and regulatory T cells and blood-derived inflammation-resolving M2 cells (Raposo et al., 2014). Using an acute SCI model, they showed that peripheral Th1 effector cells play an important role at the initial stage after injury by activating the remote epithelial blood–cerebrospinal fluid barrier to allow leukocyte trafficking and recruitment of M2 cells to the spinal cord. Further, mice deficient in Th1 cells exhibited reduced infiltration of M2 cells in the injured cord. In contrast, infiltration of M2 cells was critical for recruitment of regulatory T cells to the injured cord. Most importantly, while reduction of regulatory T cells at the early stage following injury had a beneficial effect on the repair process, their ablation at the subacute/chronic phase interfered with tissue remodeling. These data illustrate the existence of a dynamic immune cell network essential for repair, acting at discrete stages and involving effector and regulatory T cells, as well as blood-derived macrophages, calling for carefully controlled therapeutic interventions both temporally and spatially. A fine balance between effector and regulatory T cells is desirable throughout the recovery phase, with a need to shift the bias in favor of effector T cells at the initial stages post-injury, and toward regulatory T cells at the subacute/chronic phases when tissue remodeling occurs. Such changes in the cellular balance may be achieved either by active vaccination or by well controlled depletion of regulatory T cells (Raposo et al., 2014). Manipulation of the immune response is rather intriguing and several studies have emerged attempting to stop M1 polarization, inhibit macrophage proliferation, reprogram macrophages toward an M2 phenotype and transplant macrophages or cells that would influence macrophage fate (Fig. 4) [for review see Gensel et al. (2011) and Ren and Young (2013)]. However, modulating the immune response definitely needs caution since, for example, excessive or prolonged M2 polarization may lead to unwanted fibrotic responses and scarring (Murray and Wynn, 2011). Also translating the results from mouse studies to the human situation might reveal significant divergence but also potential human-specific features (David and Kroner, 2011; Martinez et al., 2006; Ren and Young, 2013). Manipulation of the Glial Scar A major event occuring upon CNS injury is activation of astrocytes and formation of the glial scar. Reactive astrocytes are hypertrophic with altered metabolism and increased levels of protein expression, such as glial fibrillary acidic protein (GFAP), but also proteins of the extracellular matrix (ECM), Volume 63, No. 7


such as laminin and CSPGs which contribute to scar formation (Busch and Silver, 2007; Silver and Miller, 2004). Apart from astrocytes, other cell types including pericyte-derived fibrotic cells (Goritz et al., 2011), OPCs and meningeal fibroblasts (Afshari et al., 2009) are also partners in the glial scar. Interestingly, M1 macrophages express 17-fold higher levels of CSPGs than M2 polarized cells (Martinez et al., 2006). The role of the glial scar in the injured CNS is both beneficial and detrimental depending on the time course. At early stages after injury, the glial scar acts protectively by establishing a boundary between damaged and spared neural tissue (Bush et al., 1999; Faulkner et al., 2004; Okada et al., 2006) while recently the scar has also been considered as immunoregulatory [for review see Raposo and Schwartz (2014)]. During the chronic phase, the glial scar forms a physical and chemical barrier to axonal regeneration and remyelination (Rolls et al., 2008, 2009). Any therapeutic intervention targeting the glial scar would be foreseeable at the chronic phase after injury, coincident with the resolution of the inflammatory response and the occurrence of tissue remodeling and remyelination. By contrast, inhibition of CSPG synthesis in the acute phase leads to increased tissue loss and impaired locomotor recovery, causing a dramatic effect on the spatial organization of the blood-derived immune cells around the lesion site, decreased IGF-1 production by microglia/macrophages and increased TNF-a levels (Rolls et al., 2008). Is though the glial scar a useful target for manipulation to enhance remyelination? The answer is not that simple. Reactive astrocytes are known to release TNF-a and bone morphogenetic proteins that inhibit OPC survival and differentiation (Su et al., 2011; Wang et al., 2011b). However, without astrocytes OPCs fail to remyelinate the adult demyelinated spinal cord (Nash et al., 2011; Talbott et al., 2005). In contrast, high levels of extracellular matrix molecules, such as CSPGs, fibronectin, hyaluronan, collagen and tenascin C, present in the glial scar, impede remyelination by inhibiting the survival, proliferation and migration of OPCs, and their maturation to myelinating OLs (Lau et al., 2012, 2013; Sherman and Back, 2008; Siskova et al., 2006; Stoffels et al., 2013; van Horssen et al., 2007). The receptor protein tyrosine phosphatase sigma (RPTPr) binds CSPGs with high affinity and mediates the inhibitory effects of CSPGs on cells of the OL lineage via a Rho-kinase associated downstream signaling pathway providing new therapeutic targets (Pendleton et al., 2013). Enzymatic removal of glycosaminoglycan chains off the core protein of CSPGs using chondroitinase ABC (chABC) enhances axonal regeneration (Bradbury et al., 2002; Lee et al., 2010b) and remyelination (Fig. 4) (Siebert and Osterhout, 2011; Siebert et al., 2011). Large scale CSPG digestion with chABC gene therapy using a lentiviral vector July 2015

to deliver the enzyme acutely in the contused rat spinal cord leads to reduced pathology and modulates macrophage phenotype in favor of M2 polarization (Bartus et al., 2014). ChABC treatment has been combined with other interventions, such as cell transplantation, and growth factor and/or neurotrophin administration [reviewed in Zhao and Fawcett (2013)], but also with biomaterials such as hydrogelmicrotubes while enzyme thermostabilization has been tried for sustained activity and controlled local release without the need of a gene therapy approach (Hyatt et al., 2010; Lee et al., 2010b; Pakulska et al., 2013; Rossi et al., 2012). These applications have demonstrated reduced levels of CSPGs, enhancement of fiber regeneration and functional recovery. However, considering that CSPG expression is desirable at the early stages after SCI, the timing of intervention is a critical factor.

Cell Transplantation: Solo or Combined Santiago Ramon y Cajal (1928) and his disciple Francisco Tello (1911) were the first to indicate that CNS axons can be myelinated by exogenous cells. This idea remained dormant for more than half a century, until publication of landmark studies showing that peripheral nerve grafts and purified SCs could remyelinate the injured spinal cord. Approaches that involve cell transplantation have since gained considerable attention for treatment of the injured spinal cord. Franklin et al. demonstrated that transplanted olfactory ensheathing cells could also remyelinate the demyelinated CNS (Franklin et al., 1996), while stem cells derived from neural or embryonic tissues were identified as promising sources for cellular grafts (Brustle et al., 1999; Hammang et al., 1997), opening the field of cell therapy approaches based on embryonic stem cell (ES)- and induced pluripotent stem (iPS) cell-derived cells. Transplantation of myelinating cells, their precursors, or multipotent cells steered toward a myelinating phenotype can augment recovery (Lavdas et al., 2008, 2011; Nakamura and Okano, 2013; Tetzlaff et al., 2011) and promote remyelination (Fig. 4) (Fouad et al., 2005; Hawryluk et al., 2014; Yasuda et al., 2011; Zujovic et al., 2010). The complex changes occurring in spinal cord tissue following injury have led to the idea of using combinatorial strategies involving cellular grafts together with administration of neuroprotective agents and growth factors, bioartificial guidance channels, and other tissue engineering products, such as biocompatible scaffolds or hydrogels to bridge cavities and cysts and support regrowing axons, enzymatic removal of inhibitory molecules present in the glial scar, or elevation of cyclic adenosine monophosphate (cAMP) to enhance remyelination [reviewed in (Lavdas et al., 2008, 2011; Tetzlaff et al., 2011; Wiliams and Bunge, 2012)]. In the course of these studies it was revealed that the beneficial effects of transplanted cells are not 1113

limited to replacement of damaged cells, but extend to their remarkable neuroprotective and immunomodulatory capacities within the injured cord (Cossetti et al., 2014; Cusimano et al., 2012; Drago et al., 2013; Nakajima et al., 2012; Pluchino and Cossetti, 2013). The choice of the appropriate cell types to be used for transplantation is still under investigation so that the graft fulfills ethical and safety concerns, ease of availability, and avoidance of rejection. Ideally, autologous cell transplantation overriding graft rejection may be beneficial both early for providing neuroprotection and immunomodulation and later for enhancing tissue remodelling. Several clinical trials are ongoing but the results are still indicative of the need for further research (Harrop et al., 2012). A brief account of selective cell types used for transplantation is given below. Neural Stem/Precursor Cells and OL Lineage Cells Cells of the oligodendroglial lineage, such as OPCs and premyelinating OLs, are most obvious candidates for cell transplantation aiming at remyelination after SCI (Czepiel et al., in press) and pre-clinical studies have confirmed the plausibility of such an approach (Cao et al., 2005, 2010). Methods have been described for isolation of human OPCs (Miron et al., 2008; Roy et al., 1999; Ruffini et al., 2004; Windrem et al., 2002), however, the limited availability of embryonic human tissue represent a serious drawback. Indeed, in clinical terms there is no suitable source of autologous OPCs whilst heterologous transplantation would require long-term immunosuppression, undesirable in time points where a functional immune system is required for remyelination. Embryonic or adult neural stem/precursor cells (NPCs) constitute an alternative source of transplantable cells. NPCs are self-renewable, multipotent cells that upon differentiation generate neurons, astrocytes, and OLs. NPCs are regarded as cells of high therapeutic interest for a variety of neurological diseases, including those affecting myelin, as well as CNS injuries. Numerous studies have characterized the potential of these cells after transplantation in SCI models with encouraging outcome (Karimi-Abdolrezaee et al., 2006, 2012; Plemel et al., 2011). ES cells and more recently iPS cells may also be directed to yield transplantable NPCs and/or OPCs and the myelination potential of these cells has been attested in several studies (Fig. 4) (Brustle et al., 1999; Cloutier et al., 2006; Erceg et al., 2010; Faulkner and Keirstead, 2005; Keirstead et al., 2005; Marques et al., 2010; Nistor et al., 2005). Most interestingly, it was documented that the advantages of NPCs after transplantation are not limited to their ability to replace damaged CNS cells but extend to their immunomodulatory and tissue trophic functions exerted by secretion of homeostatic molecules often utilizing extracellular vesicles (Cossetti et al., 2014; Pluchino and Cossetti, 2013) that ultimately reduce 1114

tissue damage and/or enhance endogenous repair, potentially affecting remyelination in an indirect way (Cossetti et al., 2014; Cusimano et al., 2012; Drago et al., 2013; Nakajima et al., 2012; Pluchino and Cossetti, 2013). As much as the grafted cells exert their influence to the host environment, it has become apparent that the reverse is also true, with the properties and vulnerability of the transplanted cells depending on the host microenvironment (Kumamaru et al., 2012; Sontag et al., 2014). The promising outlook of human ESC-derived OPC transplantation into the injured rat spinal cord performed by Keirstead et al. (2005) opened the way toward clinical development. Geron Corporation obtained FDA approval for a Phase I Clinical Trial for safety assessment of its human ESCderived OPC product, GRNOPC1, in SCI patients (Alper, 2009; Geron, 2009). To obtain clearance, Geron addressed extensive regulatory concerns surrounding its GRNOPC1 product through preclinical studies of nearly 2,000 rodents with SCI and submitted the largest ever investigational new drug filing in the FDA’s history, over 22,000 pages. When the trial was eventually launched in 2010, it raised great expectations in patients, the scientific community and related industry. One year later and after having enrolled four patients, Geron suddenly announced that it dropped the study due to financial concerns (Frantz, 2012). The Geron case raised major ethical and social questions regarding the secure commitment needed by any company that starts a human trial to finish it, unless for safety and scientific reasons (Frantz, 2012; Scott and Magnus, 2014). Nevertheless, the first results announced by a suitor company after 3 years of clinical follow-up of the participating patients were hopeful in that they revealed no indications for safety concerns. Inspired by the 2012 Nobel prize award to Sir John Gurdon and Shinya Yamanaka for their groundbreaking discovery that mature cells may be reprogrammed to become pluripotent, research based on iPS cells has been intensified. These cells carry great expectations in the field of regenerative medicine as they can be derived from a patient’s own somatic cells, expanded and used for autologous transplantation (Takahashi et al., 2007). With the introduction of iPS cells, two major obstacles were defeated: graft rejection due to allogeneic transplantation and ethical concerns arising from the use of aborted fetal tissue. Transplantation of human iPS cellderived NPCs in the mouse but also in the common Marmoset (non-human primate) injured spinal cord promoted angiogenesis, axonal regrowth and myelin restoration leading to improved functional recovery, without tumor formation (Kobayashi et al., 2012; Nori et al., 2011). Grafted iPS cellderived NPCs differentiated into all three major neural cell types (neurons, astrocytes, and OLs) to exert their beneficial function, but were also found to promote the survival, Volume 63, No. 7


differentiation and remyelination capacity of host OPCs and OLs via secretion of leukemia inhibitory factor (LIF) (Laterza et al., 2013). iPS cells have also been differentiated in vitro to pure suspensions of functional OPCs (Czepiel et al., 2011) capable to myelinate in vivo the brains of congenitally myelin-deficient shiverer mice (Wang et al., 2013). The limited migration of iPS cell-derived OPCs can be ameliorated by overexpression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) (Czepiel et al., 2014) as previously shown for other myelinating cell types (Lavdas et al., 2006). The iPS cell technology is indeed very promising for many clinical applications of neurological interest but obstacles that have to be eliminated before assessing their efficacy is the use of genome integrating genetic manipulation inherent to their production (Okano et al., 2013), the long and cumbersome reprogramming and redifferentiation protocols and the high-risk for teratoma-formation due to remaining undifferentiated iPS cells even after exhaustive differentiation and cell sorting. Direct lineage conversion of somatic cells to NPCs would bypass some of these problems and at the same time provide an expandable cellular source that would yield desirable numbers of transplantable cells. Direct derivation of NPCs from mouse fibroblasts has been accomplished through different curtailed versions of reprogramming (Han et al., 2012; Kim et al., 2011; Lujan et al., 2012; Ring et al., 2012; Thier et al., 2012). Moreover, by forced expression of three transcription factors, mouse and rat fibroblasts were directly reprogrammed to functional OPCs with properties similar to primary OPCs in terms of morphology and gene expression signatures (Yang et al., 2013). The translation to lineage conversion of human fibroblasts to OPCs is pending. Despite the new option provided by direct reprogramming for faster and efficient generation of therapeutically relevant cells, a number of hurdles are still to overcome, such as lack of purity of the differentiated population, stochastic events involved in the conversion process, and the residual epigenetic memory from the original cell type (Kim et al., 2012). Schwann Cells Historically, SCs were the first type of cells used for transplantation in the injured spinal cord because of their inherent properties to sustain the development and regeneration of peripheral nerves and their capacity to myelinate CNS axons. As discussed above, their involvement in spontaneous CNS remyelination is more significant than previously thought. SCs are appealing candidates for autologous transplantation as they may be easily obtained and expanded from human peripheral nerve biopsies (Fig. 4) (Levi et al., 1995). Additionally, SCs and peripheral myelin are most probably not a target in MS, therefore lessons from SCI may have a wider impact for the use of these cells in CNS white matter diseases July 2015

(Kocsis and Waxman, 2007). A number of studies have demonstrated the efficacy of these cells after transplantation in the injured CNS, either alone or in combination with other treatments (Bachelin et al., 2005; Girard et al., 2005; Lavdas et al., 2008, 2011; Tetzlaff et al., 2011; Wiliams and Bunge, 2012) culminating their use in humans. Transplantation of autologous human SCs in patients with subacute SCI has been listed for a Phase I clinical trial for assessing safety and tolerability (Guest et al., 2013). Skin-derived precursors (SKPs) constitute a potential and less invasive source for obtaining SCs (Fig. 4). By lineage tracing in the mouse and by transcriptome comparison both in mouse and human, it was demonstrated that SKPs can be generated from neural crest-derived facial and mesodermally derived foreskin dermis and that SKPs of both origins can give rise to myelinating SCs (Biernaskie et al., 2006; Krause et al., 2014). This is achieved without a need for genetic manipulation, unlike the derivation of SCs from human ES or human iPS cells (Lee et al., 2010a; Liu et al., 2012b; Wang et al., 2011a). An important issue is that naive SCs do not intermingle well with astrocytes (Kocsis and Waxman, 2007) and therefore a number of preclinical studies have used genetically modified SCs to improve their migration and integration in the CNS. For example, SCs have been genetically modified to secrete chondroitinase or growth/neurotrophic factors and have been combined with simultaneous transplantation of other cell types, such as olfactory ensheathing cells or mesenchymal stem cells (Tetzlaff et al., 2011; Wiliams and Bunge, 2012) with significantly improved results. Our strategy for ameliorating the therapeutic potential of SCs was to alter their adhesive properties by expressing the polysialylated form of NCAM (PSA-NCAM) on their surface. In vitro, rodent PSA-NCAM expressing SCs showed enhanced survival and migration as well as a better capacity to mix with astrocytes without impairment of their myelinating ability (Lavdas et al., 2006; Luo et al., 2011; Papastefanaki et al., 2007) despite the inhibitory role of axonally expressed PSA-NCAM on myelination (Charles et al., 2000). When transplanted in acute mouse SCI, improved locomotor recovery was accompanied by increased recruitment of host OPCs and SCs, enhanced remyelination, and regeneration of serotonergic fibers (Papastefanaki et al., 2007). The beneficial results of transplantation of PSA-NCAM expressing SCs in the injured spinal cord were confirmed in the rat (Ghosh et al., 2012; Luo et al., 2011) and further by transplantation of adult macaque PSA expressing SCs in the demyelinated spinal cord of nude mice (Bachelin et al., 2010), indicating the validity of this approach. In another approach aiming to render SCs more “friendly” to the CNS environment, these cells were genetically modified to overexpress the L1 cell adhesion molecule and/or its soluble form L1-Fc (Lavdas et al., 1115

2010a,2010b) with beneficial effects after transplantation in mouse SCI. These studies indicated that the modifications induced by PSA-NCAM or L1 in SCs increased the plasticity of the local CNS microenvironment after transplantation making it more permissive to regeneration and remyelination (El Maarouf et al., 2006; Lavdas et al., 2011). In support, small molecules or peptides mimicking the function of PSA have been tried with positive outcome (Loers et al., 2014; Mehanna et al., 2010). In another recent promising approach, SCs were genetically modified to secrete a bifunctional neurotrophin (D15A) that binds to both TrkB and TrkC receptors mimicking the effects of NT3 and BDNF (Cao et al., 2005) and were used in conjunction with chABC in a rat subacute contusion SCI model resulting in enhanced locomotor recovery, remyelination and axonal regeneration (Kanno et al., 2014). Olfactory Ensheathing Cells Olfactory ensheathing cells (OECs) are a distinct population of cells that wrap around, but do not myelinate, the axons of olfactory receptor neurons in their entire length as they extend from the olfactory epithelium in the PNS to the olfactory bulb in the CNS. OECs can be easily isolated from the olfactory mucosa, though recent data claim that more potent OECs may be isolated from the olfactory bulb (Fig. 4), but through a procedure that requires craniotomy (Barnett et al., 2000; Guerout et al., 2010; Markakis et al., 2009). Unlike SCs, OECs intermingle efficiently with astrocytes (Lakatos et al., 2000). Although OECs do not myelinate the axons of olfactory receptor neurons in situ, they can remyelinate the injured CNS and confer functional restoration in animal models of SCI (Kocsis et al., 2009; Lankford et al., 2008; Radtke et al., 2008; Sasaki et al. 2004,2006a,2006b,2007,2011). OECs have been used for transplantation in combination with SCs since the two cell populations have complementary functions and could thus act synergistically toward an improved outcome (Sun et al., 2013). OECs are under clinical trials and recently the functional regeneration of supraspinal connections was reported (Tabakow et al., 2014) in a 38-year-old man with thoracic spinal cord transection suffering paralysis from the chest down (classified as clinically complete SCI ASIA-A). Twentyone months after injury the patient received a combinatorial treatment involving OEC transplantation into the spinal cord with peripheral nerve bridging using strips of autologous sural nerve following resection of the glial scar, with post-operative MP treatment. No adverse effects were noted 19 months after surgery and the patient improved from ASIA A to ASIA C (incomplete neurological function). The neurophysiological measurements indicated long-distance motor fiber regeneration possibly from the corticospinal tracts and remyelination of these tracts, mainly occurring from the part of the spinal 1116

cord that was bridged with the peripheral nerve strips (Tabakow et al., 2014). However, it is noteworthy that this patient had a defined knife injury, which may not reflect the more common traumatic haemorrhagic SCI where a greater amount of tissue is damaged. Additionally, the patient received intense rehabilitation and this alone may have played a significant role in the outcome of this specific case. Despite the need for systematic evaluation of the efficacy and safety of this approach in more patients, this study underlines the potential of a multicombinatorial approach for the successful treatment of human SCI.

Concluding Remarks Despite intensive research over the past three decades, functional restoration after SCI remains an important challenge. Investigations have addressed a multitude of events taking place at critical stages after SCI and have delineated the underlying molecular mechanisms. Nevertheless, understanding myelin pathology and devising means to halt demyelination and enhance remyelination are important issues, still under investigation. New significant findings regarding the complex roles of the innate and adaptive immune responses to injury and the mutual interactions between neuronal activity and oligodendrogenesis/myelination open new prospects for the design of improved therapeutic strategies aiming at time- and target-specific interventions. However, given the complexity of SCI pathology, it has become apparent that a single approach is not sufficient to restore functionality. Combinatorial strategies aiming at elimination of conduction block, protection of OLs and myelin at early stages, and boosting remyelination at the chronic stage may provide maximal advantage. A wide array of tools based on biotechnology, nanotechnology, cell and tissue engineering provides additional opportunities for SCI repair. Although translation to human may reveal unexpected complications due to divergence from animal models, current and future research should bring us closer to SCI therapies.

Acknowledgment Grant sponsor: Greek Ministry of Education; Grant number: COOPERATION/09SYN-21–969; EXCELLENCE I-2272; Grant sponsor: Empeirikion Foundation; Grant number: KRIPIS-MIS450598. Authors thank Era Taoufik and Dimitra Thomaidou for stimulating discussions and critical comments on the manuscript.

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Papastefanaki and Matsas: Myelin Repair in Spinal Cord Injury Franklin RJ, Gallo V. 2014. The translational biology of remyelination: Past, present, and future. Glia 62:1905–1915.

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Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination.

Experimental demyelination and remyelination of murine spinal cord by focal injection of lysolecithin.

Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury.

Remyelination after spinal cord injury: is it a target for repair?

Hydrogels and Cell Based Therapies in Spinal Cord Injury Regeneration.

Aberrant remyelination of axons after heat injury in the dorsal funiculus of rat spinal cord.

Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord.

Toward a health services research capacity in spinal cord injury.

Chronic oligodendrogenesis and remyelination after spinal cord injury in mice and rats.

Remyelination improvement after neurotrophic factors secreting cells transplantation in rat spinal cord injury.

Complete spinal cord injury: an indication for spinal cord stimulation?

Hypothermia for spinal cord injury.

Toward the prediction of neurological injury from tethered spinal cord: investigation of cord motion with magnetic resonance.

Immune modulatory therapies for spinal cord injury--past, present and future.

Grafted Human iPS Cell-Derived Oligodendrocyte Precursor Cells Contribute to Robust Remyelination of Demyelinated Axons after Spinal Cord Injury.

Walking Index for Spinal Cord Injury version II in acute spinal cord injury: reliability and reproducibility.

Return to work following spinal cord injury.

Spinal cord injury rehabilitation.

Spinal cord injury rehabilitation.

Spinal cord injury pain.

Acute spinal-cord injury.

Relationship between Spinal Cord Volume and Spinal Cord Injury due to Spinal Shortening.

Early access to vocational rehabilitation for spinal cord injury inpatients.

Current pregnancy among women with spinal cord injury: findings from the US national spinal cord injury database.