Microenvironmental regulation of oligodendrocyte replacement and remyelination in spinal cord injury

Abstract

Myelin is a proteolipid sheath enwrapping axons in the nervous system that facilitates signal transduction along the axons. In the central nervous system (CNS), oligodendrocytes are specialized glial cells responsible for myelin formation and maintenance. Following spinal cord injury (SCI), oligodendroglia cell death and myelin damage (demyelination) cause chronic axonal damage and irreparable loss of sensory and motor functions. Accumulating evidence shows that replacement of damaged oligodendrocytes and renewal of myelin (remyelination) are promising approaches to prevent axonal degeneration and restore function following SCI. Neural precursor cells (NPCs) and oligodendrocyte progenitor cells (OPCs) are two main resident cell populations in the spinal cord with innate capacities to foster endogenous oligodendrocyte replacement and remyelination. However, due to the hostile microenvironment of SCI, the regenerative capacity of these endogenous precursor cells is conspicuously restricted. Activated resident glia, along with infiltrating immune cells, are among the key modulators of secondary injury mechanisms that create a milieu impermissible to oligodendrocyte differentiation and remyelination. Recent studies have uncovered inhibitory roles for astrocyte‐associated molecules such as matrix chondroitin sulfate proteoglycans (CSPGs), and a plethora of pro‐inflammatory cytokines and neurotoxic factors produced by activated microglia/macrophages. The quality of axonal remyelination is additionally challenged by dysregulation of the supportive growth factors required for maturation of new oligodendrocytes and axo‐oligodendrocyte signalling. Careful understanding of factors that modulate the activity of endogenous precursor cells in the injury microenvironment is a key step in developing efficient repair strategies for remyelination and functional recovery following SCI.

Abbreviations

CSPGs

chondroitin sulfate proteoglycans

IGF

insulin‐like growth factor

IL

interleukin

LAR

leukocyte common antigen‐related phosphatase receptor

LIF

leukemia inhibitory factor

MS

multiple sclerosis

Nrg‐1

neuregulin‐1

NPCs

neural precursor cells

OPCs

oligodendrocyte precursor cells

RPTP‐σ

receptor protein tyrosine phophatase‐sigma

SCI

spinal cord injury

TGF

tumour growth factor

TNF

tumour necrosis factor

Introduction

Myelin sheath is composed of consecutive layers of plasma membrane that enwrap axons in the nervous system. Myelin facilitates rapid signal transmission along the axons by electrical insulation of axolemma (Stephanova, 1990; Dai et al. 2003; Wilkins et al. 2003). In the central nervous system (CNS), oligodendrocytes are responsible for myelin formation and maintenance. Loss of oligodendrocytes and consequent demyelination are hallmarks of spinal cord injury (SCI) pathophysiology that results in axonal dysfunction and degeneration (Casha et al. 2001 a; Beattie et al. 2002; Plemel et al. 2014; Alizadeh et al. 2015). Renewal of the lost myelin sheath (remyelination) around the injured spinal cord axons has been shown to enhance functional recovery by improving axonal conduction and attenuating chronic axonal degeneration (Stephanova, 1990; Dai et al. 2003; Wilkins et al. 2003; Saab et al. 2013; Stiefel et al. 2013).

Resident adult oligodendrocyte progenitor cells (OPCs) and neural precursor cells (NPCs) possess the intrinsic potential to replenish damaged oligodendrocytes. However, their ability to generate mature myelinating oligodendrocytes and ensheath axons is challenged by the inhibitory nature of the post‐injury microenvironment (Karimi‐Abdolrezaee et al. 2010, 2012; Su et al. 2011; Wang et al. 2011). Also challenging, the newly formed myelin lacks optimal thickness and the quality to restore normal electrophysiological properties of axons resulting in persistent axonal dysfunction (Nashmi & Fehlings, 2001 a; Powers et al. 2012). Replacement of oligodendrocytes and axon remyelination are highly influenced by extrinsic factors present in the injured milieu of SCI (Siebert & Osterhout, 2011; Wang et al. 2011; Dyck et al. 2015) (summarized in Figs 1 and 2). Emerging evidence has shown that the inhibitory nature of the SCI microenvironment is caused by an imbalance of promoting and inhibitory factors chiefly driven by activated glia and degenerating myelin (Kotter et al. 2006; Cregg et al. 2014; Dyck et al. 2015).

Figure 1. The molecular inhibitors and activators of oligodendrocyte lineage development and myelination .

A–E, schematic diagram shows growth factors and cytokines that promote OPC survival and proliferation (A), oligodendrocyte differentiation (B), oligodendrocyte survival (C) and maturation (D), and myelination/remyelination (E) (Almazan et al. 1985; Matthieu et al. 1992; Barres et al. 1993; Vos et al. 1996; Woodruff & Franklin, 1997; Calver et al. 1998; Hinks & Franklin, 1999; Baron et al. 2000; Arnett et al. 2001; Buonanno & Fischbach, 2001; Calaora et al. 2001; Valerio et al. 2002; Falls, 2003; Frost et al. 2003; Knapp & Adams, 2004; Foote & Blakemore, 2005; Chen et al. 2006; Du et al. 2006; Hapner et al. 2006; Hohlfeld et al. 2007; Vana et al. 2007; Zawadzka & Franklin, 2007; Brinkmann et al. 2008; Hu et al. 2008; Van't Veer et al. 2009; Xiao et al. 2010; Breton & Mao‐Draayer, 2011; Fricker et al. 2011; Gauthier et al. 2013; Peferoen et al. 2014; Dyck et al. 2015). F–I, examples of inhibitory factors that impair oligodendrocyte lineage survival, proliferation (F), differentiation (G) and myelination (I) (Mi et al. 2005; Kotter et al. 2006; Syed et al. 2011; as reviewed by Peferoen et al. 2014; Zhang et al. 2015). EGF, epidermal growth factor; CNTF, Ciliary neurotrophic factor.

Figure 2. Signalling mechanisms of oligodendrocyte fate specification and maturation .

Schematic diagram showing identified extracellular and intracellular signals involved in regulation of NPCs and OPCs. A, endothelin‐1 (ET‐1) is a soluble factor produced by reactive astrocytes that increases astrocyte expression of Jagged1 (a Notch signalling ligand). Astrocyte derived Jagged‐1 activates Notch signalling in OPCs, and inhibits oligodendrocyte differentiation and remyelination (Hammond et al. 2014). B, LIF promotes OPC differentiation and remyelination through activation of STAT‐3 signalling in OPCs (Mayer et al. 1994; Rittchen et al. 2015). C, CSPGs inhibit oligodendrocyte growth and myelination through LAR and RPTP‐σ signalling pathways and activation of Rho/ROCK pathway in both NPCs and OPCs (Lau et al. 2012; Pendleton et al. 2013; Dyck et al. 2015). D, Nrg‐1 and its signalling receptors form a major regulatory network of oligodendrocyte development and maturation. Nrg‐1 can bind to ErbB3 and ErbB4 with high affinity (Carraway & Cantley, 1994). Upon binding to Nrg‐1, ErbB receptors can form homo‐ or heterodimers and activate multiple pathways through their intracellular tyrosine kinase domain. Nrg‐1 signalling has been shown to activate Jak/STAT, Erk/MAPK and PI3/Akt that are associated with cell survival, proliferation and differentiation (Gambarotta et al. 2004; Shyu et al. 2004; Liu X et al. 2006; Li et al. 2007, 2015; Brinkmann et al. 2008; Mei & Xiong, 2008; Guo et al. 2010; Pirotte et al. 2010; Syed et al. 2010; Jabbour et al. 2011; Liu Z et al. 2011; Ortega et al. 2012; Tao et al. 2013; Gauthier et al. 2013). However, the impact of each specific ErbB receptor in mediating Nrg‐1 effects on each stage of oligodendrocyte lineage development and myelination remains to be elucidated.

In this review, we will discuss: (1) the response of resident OPCs and NPCs to tissue injury and their contribution to spontaneous oligodendrocyte replacement and remyelination in the injured spinal cord; (2) the role of activated astrocytes and scar‐associated molecules such as chondroitin sulfate proteoglycans (CSPGs) and their signalling pathway in oligodendrocyte replacement and remyelination following injury, (3) the impact of activated microglia and infiltrating peripheral immune cells, particularly macrophages, in orchestrating detrimental and beneficial changes in the post‐injury milieu, and (4) how impaired expression of supportive growth factors for oligodendrocyte development and maturation affects remyelination after injury by focusing on the role of neuronal neuregulin‐1 (Nrg‐1). Although these concepts are relevant to the majority of CNS pathologies, this review will focus primarily on SCI.

Role of myelin and oligodendrocytes in neuronal function

Myelin is composed of multiple layers of oligodendrocyte plasma membrane ensheathing axons in segments (Barres et al. 1993). A node of Ranvier is part of the axolemma located between two neighbouring myelin segments that contains voltage‐gated Na⁺ channels (Amor et al. 2014; also reviewed by Alizadeh et al. 2015). Myelin sheath conceals voltage‐gated K⁺ channels at the juxtaparanodal regions and separates them from nodal Na⁺ channels through paranodal myelin loops (reviewed in Alizadeh et al. 2015). The precise localization of ion channels along myelinated axons ensures proper action potentials (Kopysova & Debanne, 1998; Migliore et al. 1999; Nashmi & Fehlings, 2001 b). Myelin also provides insulation against electrical current, thereby electrical impulses jump from one node of Ranvier to the next one depolarizing the axon consecutively at each node resulting in ‘saltatory conduction’ (Ohno et al. 2011). Delicate structural organization of myelin sheath and ion channels in axonal membrane enables energy‐efficient and rapid signal transmission through myelinated axons (Frankenhaeuser & Schneider, 1951; Bishop & Levick, 1956; Homma et al. 1983; Saab et al. 2013; Stiefel et al. 2013). Moreover, trophic signals provided by oligodendrocytes are critical for axonal survival and growth (Dai et al. 2003; Wilkins et al. 2003).

Axon demyelination (loss of myelin sheath) occurs following oligodendrocyte death caused by trauma, autoimmune disorders, infections, genetic defects or idiopathic reasons (Zimmerman, 1956; Popescu & Lucchinetti, 2012; Kutzelnigg & Lassmann, 2014). Demyelination disrupts the precise organization of ion channels in the axolemma causing ionic imbalance and high energy consumption for signal conduction (Andrews et al. 2006; Saab et al. 2013). Increased energy demand together with loss of trophic support from oligodendrocytes, can increase the susceptibility of demyelinated axons to loss of energy homeostasis, oxidative stress and degeneration (Bristow et al. 2002; Sheng & Cai, 2012; for further information regarding the role of myelin in axonal physiology read Alizadeh et al. 2015). Therefore, oligodendrocyte replacement and axon remyelination are vital repair mechanisms for restoring function following SCI.

Oligodendrocyte death and demyelination following spinal cord injury

Spinal cord injury (SCI) results in an initial decline in oligodendrocytes through necrosis caused by the primary mechanical injury (as reviewed by Dewar et al. 2003; Almad et al. 2011). As injury progresses, the secondary injury cascades activate apoptotic pathways in oligodendrocytes (Crowe et al. 1997; Casha et al. 2001 b; Dewar et al. 2003; Dent et al. 2015). As a result, apoptosis‐mediated oligodendrocyte death continues to diminish the population of mature oligodendrocytes in sub‐acute and chronic stages of SCI (Grossman et al. 2001; Casha et al. 2001 b; Dewar et al. 2003; Almad et al. 2011). Among the most prominent secondary injury mechanisms that contribute to oligodendrocyte death following SCI are: oxidative stress caused by vascular damage and ischaemia (Thorburne & Juurlink, 1996; Xu et al. 2004; Dent et al. 2015), ATP and glutamate mediated excitotoxicity (Xu et al. 2004; Gudz et al. 2006; Matute et al. 2007), neuroinflammation, autophagy (Kanno et al. 2009), toxic blood components and proteolytic tissue enzymes (Juliet et al. 2009).

Despite considerable loss of oligodendrocytes, remyelination occurs spontaneously following SCI owing to the existence of endogenous precursor cells in the adult spinal cord (Gensert & Goldman, 1997; Salgado‐Ceballos et al. 1998; Franklin & ffrench‐Constant, 2008). Adult CNS harbours endogenous populations of NPCs (neural precursor cells) and OPCs (oligodendrocyte progenitor cells) with self‐renewal properties and the ability to replace damaged oligodendrocytes upon traumatic injury or inflammation‐induced demyelination (Weiss et al. 1996; Horner et al. 2000; Barnabe‐Heider et al. 2010). However, in more severe forms of injuries, the endogenous response of spinal cord precursor cells is not sufficient to replenish the magnitude of oligodendrocyte loss after SCI resulting in inadequate remyelination and functional deficits (Beattie et al. 1997; Crowe et al. 1997; Salgado‐Ceballos et al. 1998; Keirstead & Blakemore, 1999; Nashmi et al. 2000; Nashmi & Fehlings, 2001 b; Almad et al. 2011). Upregulation of factors known to inhibit remyelination is one underlying cause of limited recruitment of endogenous NPCs and OPCs into demyelinating lesions, which is a prerequisite for oligodendrocyte renewal and remyelination (Karimi‐Abdolrezaee et al. 2010, 2012; Lau et al. 2012). Other challenging obstacles to proper restoration of axonal function are the abnormal thinning and shorter internodes of the new myelin sheath after SCI or chronic autoimmune conditions with repeated demyelination episodes such as multiple sclerosis (MS) (Keirstead & Blakemore, 1999; Nashmi & Fehlings, 2001 a,b; Karimi‐Abdolrezaee et al. 2006; Keough & Yong, 2013; Alizadeh et al. 2015). In the following sections, we will discuss the role of microenvironmental factors that positively and negatively affect oligodendrocyte replacement and remyelination following SCI.

Inhibitory factors involved in oligodendrocyte differentiation and remyelination

Secondary injury mechanisms following SCI trigger upregulation of inhibitory signals in the injured spinal cord that create a non‐permissive environment for survival and expansion of resident NPCs and OPCs, and hinder their capacity for oligodendrocyte differentiation (Karimi‐Abdolrezaee et al. 2010; Karimi‐Abdolrezaee & Eftekharpour, 2012; Dyck & Karimi‐Abdolrezaee, 2015; Dyck et al. 2015). Emerging evidence from our group and others has shown that astrocytic differentiation is the predominant fate of NPCs in the post‐SCI milieu (Mothe & Tator, 2005; Meletis et al. 2008; Barnabe‐Heider et al. 2010; Karimi‐Abdolrezaee et al. 2010, 2012). Interestingly, genetic labelling of NPC progenies in the adult injured spinal cord has provided evidence pointing to the contribution of NPC‐derived astrocytes to the formation of the glial scar following SCI (Meletis et al. 2008; Barnabe‐Heider et al. 2010; Sabelstrom et al. 2013). In contrast to NPCs, adult OPCs contribute more prominently to oligodendrocyte replacement after injury; however, the long‐term survival and maturation of OPCs to fully myelinating oligodendrocytes is also limited in SCI milieu (Ohori et al. 2006; Almad et al. 2011). These limitations collectively result in persistent demyelination and hypo‐myelination associated with functional impairments following SCI (Buntinx et al. 2004; Ji et al. 2006; Kotter et al. 2006; Fancy et al. 2009; Pohl et al. 2011; Plemel et al. 2013; Smith et al. 2014; Dyck et al. 2015). Over the past years, accumulating evidence has identified a repertoire of molecules and pathways expressed and activated by reactive glia that inhibit oligodendrocyte differentiation and myelination. Examples of these signalling pathways are LINGO (leucine rich repeat and Ig domain‐containing, Nogo receptor interacting protein), Wnt signalling, Semaphorin 3A (Sema3A), CSPGs, endothelin‐1 (ET‐1), Rho/ROCK and Notch signalling pathways (Ji et al. 2006; Gadea et al. 2008, 2009; Fancy et al. 2009; Ye et al. 2009; Syed et al. 2011; Lau et al. 2012; Boyd et al. 2013; Pendleton et al. 2013; Hammond et al. 2014; Dyck et al. 2015). In this review, we will focus on the role of glial scar and inflammatory associated molecules in modulating remyelination after SCI.

Modulatory role of scar‐associated CSPGs in oligodendrocyte differentiation and remyelination following SCI

SCI elicits an activation programme in astrocytes that profoundly changes their gene expression profile and morphology. One major outcome of astrocyte activation is pronounced upregulation of a number of extracellular matrix (ECM) molecules such as inhibitory CSPGs (Fitch & Silver, 2008; Bradbury & Carter, 2011; Karimi‐Abdolrezaee & Billakanti, 2012). CSPGs are an integral component of the ECM in the intact nervous system that play important roles in development and adulthood including their role in the formation of perineuronal net (PNN) and synaptic plasticity (Silver & Miller, 2004; Deepa et al. 2006; Massey et al. 2006; Dyck & Karimi‐Abdolrezaee, 2015). Following SCI, exaggerated upregulation of CSPGs by activated astrocytes in the glial scar poses inhibitory effects on axonal sprouting and regeneration, neural conduction, cell replacement and remyelination after SCI (extensively reviewed elsewhere: e.g. Bradbury & Carter, 2011; Karimi‐Abdolrezaee & Billakanti, 2012; Cregg et al. 2014; Dyck & Karimi‐Abdolrezaee, 2015). CSPGs were first identified for their potent inhibitory influence on axonal regeneration and plasticity in the injured spinal cord (Silver, 1994; Bradbury et al. 2002). However, recent work by our group and others has identified a key role for CSPGs in modulating the regenerative response of resident or exogenously grafted NPCs and OPCs in SCI and their capacity for oligodendrogenesis (Karimi‐Abdolrezaee et al. 2010, 2012) (Fig. 2). In rat compressive SCI, we demonstrated that upregulation of CSPGs in chronic lesions impedes the ability of both resident and transplanted NPCs to migrate to the lesion, differentiate to oligodendrocytes and integrate with demyelinated axons (Karimi‐Abdolrezaee et al. 2010, 2012). Degradation of CSPGs by chondroitinase ABC was sufficient to reverse these inhibitory effects and promote the outcomes of NPC transplantation in chronic SCI (Karimi‐Abdolrezaee et al. 2010, 2012). Our recent in vitro studies have shed new light on CSPG mechanisms and further corroborated our SCI findings indicating that CSPGs directly modulate the properties of spinal cord NPCs through receptor‐mediated mechanisms (Dyck et al. 2015). We have demonstrated that CSPGs regulate NPCs by signalling through two members of the protein tyrosine phosphatase (PTP) receptors, leukocyte common antigen‐related phosphatase receptor (LAR) and receptor protein tyrosine phophatase‐sigma (RPTP‐σ). Using genetic targeting approaches, we showed that exposure to CSPGs activates LAR and RPTP‐σ in adult spinal cord‐derived NPCs resulting in several inhibitory effects, including reduced NPC survival, integration, growth, proliferation and oligodendrocyte differentiation (Dyck et al. 2015). Interestingly, NPCs harvested from RPTP‐σ knockout mice or NPCs treated with LAR and RPTP‐σ small interference RNA showed less susceptibility to CSPG inhibitory effects and behaved normally (Dyck et al. 2015). Furthermore, our studies identified that CSPG signalling exerts its effects primarily through intracellular activation of the Rho/ROCK pathway as pre‐treating NPCs with Y‐27632, a specific ROCK inhibitor, was sufficient to reverse all the inhibitory effects of CSPGs on NPCs (Dyck et al. 2015). At the intracellular level, we found that CSPGs deactivate PI3K/Akt and MAPK/Erk pathways in NPCs by dephosphorylation of Erk1/2 and Akt. Of note, PI3K/Akt and MAPK/Erk pathways are two major signalling pathways involved in NPC proliferation (Chan et al. 2013), oligodendrocyte differentiation and survival (Flores et al. 2000; Rowe et al. 2012; Rafalski et al. 2013) (Fig. 2). Importantly, activation of MAPK/Erk signalling has also been associated with oligodendrocyte process growth and myelination (Flores et al. 2008; Fyffe‐Maricich et al. 2011; Ashii et al. 2012; Furusho et al. 2012), and lack of RPTP‐σ or blockade of LAR has been shown to improve remyelination, axonal growth and functional recovery following SCI (McLean et al. 2002; Thompson et al. 2003; Sapeiha et al. 2005; Shen et al. 2009; Fry et al. 2010; Fisher et al. 2011) (Fig. 2). In addition to NPCs, CSPGs negatively affect the ability of OPCs to migrate to demyelinating lesions and form mature myelinating oligodendrocytes in both traumatic SCI and MS‐like lesions (Kuhlmann et al. 2008; Karimi‐Abdolrezaee et al. 2010; Lau et al. 2012; Pendleton et al. 2013; Plemel et al. 2014). Studies by Yong's group have unravelled that inhibiting CSPG biosynthesis using xyloside can improve OPC migration, proliferation and remyelination in lysolecithin‐induced demyelinating lesions (Lau et al. 2012). Collectively, a wealth of evidence suggests an inhibitory role for activated astrocytes and scar‐associated CSPGs in modulating the activities of NPCs and OPCs in SCI and MS conditions (as reviewed by Dyck & Karimi‐Abdolrezaee, 2015). Upregulation of CSPGs in the glial scar is a hallmark of CNS injuries, thus targeting CSPGs offers an effective approach in combinatorial strategies aiming at activation of endogenous repair mechanisms or cell transplantation therapies in the injured or diseased CNS.

Endothelin‐1 (ET‐1) is another signalling peptide secreted by activated astrocytes following CNS injury (Jiang et al. 1993; Gadea et al. 2008) that is known for its detrimental roles in secondary injury mechanisms including disruption of the blood–spinal barrier and induction of astrogliosis (McKenzie et al. 1995; Gadea et al. 2008). Recent studies have identified an additional role for ET‐1 in inhibiting oligodendrocyte differentiation and remyelination by activating the Notch signalling pathway in OPCs, an effect that can be reversed by the use of an ET‐1 receptor pan‐antagonist (Hammond et al. 2014) (Fig. 2).

Inflammation and myelin repair

The neuro‐immune response, and in particular microglial activation, plays a vital role in modulating remyelination following SCI and MS conditions (Vela et al. 2002; Beers et al. 2011; Kokaia et al. 2012; Liu et al. 2014; Peferoen et al. 2014; Doring et al. 2015). Microglia are resident immune cells of the CNS that are involved in initiating neuroinflammation following injury. Recent studies have revealed that microglia, in concert with peripherally recruited macrophages, can modulate demyelination and remyelination in the injured CNS through multiple mechanisms. These mechanisms include clearance of myelin debris and production of cytokines and growth factors such as tumour growth factor β (TGFβ), insulin‐like growth factor (IGF)‐1 and interleukin‐10 (IL‐10) (Hinks & Franklin, 1999; Woodruff & Franklin, 1999; Gordon, 2003; Mosser, 2003; Hsieh et al. 2004; Martinez et al. 2008; Doring et al. 2015; Lampron et al. 2015; Poliani et al. 2015; Wang et al. 2015) (Fig. 1).

Following injury, activated microglia can adopt a predominantly pro‐ or anti‐inflammatory phenotype depending on the cytokine setting and immunomodulatory signals they receive from their microenvironment (Miron et al. 2013; Miron & Franklin, 2014). Their cross talk with T‐cells fosters an immunomodulatory response in microglia/macrophages through production of cytokines, signalling peptides and antigen presentation to T‐cells (Mosser, 2003; Martinez et al. 2008; Kigerl et al. 2009; Ransohoff & Brown, 2012; Codarri et al. 2013; Strachan‐Whaley et al. 2014). Recent evidence shows that depending on the phenotype of microglia, they can promote or suppress oligodendrocyte remyelination following an injury (Lalive et al. 2005; Peferoen et al. 2014; Strachan‐Whaley et al. 2014).

Pro‐inflammatory microglia are characterized by their increased expression of inflammatory cytokines such as interleukin 1 β (IL‐1β) and tumour necrosis factor (TNF‐α) (David & Kroner, 2011). TNF‐α and IL‐1β adversely affect oligodendrocyte remyelination by reducing OPC survival, proliferation and differentiation (as reviewed by Peferoen et al. 2014). Reactive oxygen and nitrogen species (ROS and NOS) produced by activated glial and other inflammatory cells will further undermine oligodendrocyte survival and myelination (as reviewed by Peferoen et al. 2014; Alizadeh et al. 2015). On the other hand, anti‐inflammatory microglia, characterized by the expression of TGFβ, arginase‐1, IL‐10, IL‐4 and IL‐13, play positive immune‐regulatory roles through interaction with T‐helper 2 (Th2) lymphocytes (Anderson & Mosser, 2002; Beers et al. 2011; Miron & Franklin, 2014). Onset of the anti‐inflammatory phenotype in microglia/macrophages has been associated with a supportive role in promoting endogenous activation of NPCs and OPCs. As an example, IL‐10 is shown to increase NPC migration (Guan et al. 2008), improve their neuronal and oligodendrocyte differentiation (Yang et al. 2009), and improve remyelination in experimental autoimmune encephalomyelitis (Pluchino & Martino, 2005; Butovsky et al. 2006) (Fig. 1). In animal models of chemical demyelination, a switch from pro‐ to anti‐inflammatory microglial phenotype has been associated with a regenerative state in which OPCs migrate to the site of demyelinating lesion and differentiate into myelinating oligodendrocytes (Miron et al. 2013). Interestingly, further studies have suggested a supportive role for anti‐inflammatory microglia in opposing the inhibitory effects of CSPGs on axonal regeneration and remyelination (Kigerl et al. 2007; Rolls et al. 2008).

Leukemia inhibitory factor (LIF) is another factor produced by T‐cells and macrophages/microglia that promotes oligodendrocyte differentiation of OPCs (Mayer et al. 1994; Rittchen et al. 2015) (Fig. 2). By opposing the inhibitory effects of IL‐6 and suppressing IL‐17 release, LIF plays major roles in the onset of self‐tolerance in the developing immune system (Gao et al. 2014). In a recent study, in vivo delivery of LIF‐bound nanoparticles immunologically targeted for neural/glia antigen 2 (NG2⁺) OPCs was associated with significant improvement in remyelination in a focal CNS demyelination model (Rittchen et al. 2015). However, there was no improvement in the thickness of the myelin in newly myelinated fibres (Rittchen et al. 2015).

Altogether, recent investigations suggest a determining role for the immune response in remyelination with both promoting and inhibitory effects (Mosser, 2003; Wee Yong, 2010; Gauthier et al. 2013). Further research is necessary to unveil the impact of immune‐regulatory signals on endogenous mechanisms of oligodendrocyte differentiation and remyelination. Given the pivotal role of immune cells in CNS injuries, this knowledge is essential in developing new therapies for myelin repair in conditions characterized by neuroinflammation such as MS, stroke and neurotrauma.

Promoting factors critical for remyelination

Following injury, optimal remyelination is further challenged by deficient expression of growth factors and neurotrophins with supportive roles in oligodendrocyte differentiation of NPCs and OPCs as well as myelin maintenance and axo‐oligodendrocyte signalling. Neuregulin‐1 (Nrg‐1), brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF), IGF‐1 and LIF are among the best‐known growth and neurotrophic factors involved in OPC survival, differentiation and remyelination (Barres et al. 1993; Calver et al. 1998; Mason et al. 2000; Butzkueven et al. 2002; Du et al. 2006; Van't Veer et al. 2009). Our recent findings in SCI have established a correlation between SCI‐induced downregulation of Nrg‐1 and limited differentiation of oligodendrocytes from endogenous precursor cells (Gauthier et al. 2013). Nrg‐1 is an axonally localized growth factor produced primarily by neurons in the CNS and the peripheral nervous system (PNS) (Mei & Xiong, 2008) (see Fig. 1). Nrg‐1 and its signalling tyrosine kinase receptors, ErbB2, ErbB3 and ErbB4 play a supportive role in Schwann cells and oligodendrocyte development, survival, maturation and myelination in the CNS and PNS (Vartanian et al. 1999; Flores et al. 2000; Brinkmann et al. 2008; Gauthier et al. 2013). Nrg‐1 is additionally involved in neuronal migration, development of synapses and neuromuscular junctions (Mei & Xiong, 2008). In a rat model of clip compression SCI, we have demonstrated that Nrg‐1 protein expression undergoes a rapid and permanent decline following injury that fails to recover to its basal levels in the subsequent stages of injury (Gauthier et al. 2013). Our studies on endogenous cell differentiation activities uncovered a strong correlation between Nrg‐1 depletion and increased astrocyte differentiation and glial scar formation following SCI (Gauthier et al. 2013). Sustained intrathecal administration of recombinant human Nrg‐1 into the injured spinal cord promoted endogenous replacement of oligodendrocyte at the expense of astrocyte differentiation (Gauthier et al. 2013). Notably, in these studies, Nrg‐1 bioavailability also exerts neuroprotective effects and enhanced preservation of the existing populations of oligodendrocytes and axons resulting in reduced tissue degeneration following SCI. Recent studies by other groups have also shown that glial growth factor 2 (GGF2 or Nrg‐1 Type IIβ3) in synergy with basic fibroblast growth factor 2 (FGF2) enhances the expansion of NG2⁺ OPCs in the injured spinal cord (Whittaker et al. 2012).

In closing, recent findings emphasize the impact of microenvironmental signals on the success of remyelination following SCI and MS conditions. The magnitude of inhibitory signals imposed to the endogenous precursor cells, and the lack of supportive factors, collectively restrict their innate ability to adequately regenerate the lost oligodendrocytes and damaged myelin following injury. Importantly, accelerating remyelination can maintain the integrity of surviving axons and attenuate chronic axonal loss following injury. Identification of key extrinsic factors involved in myelin damage and repair is a vital step in the development of effective therapeutic strategies for promoting remyelination after CNS injury or disease.

Additional information

Competing interests

None declared.

Funding

S.K.‐A. is supported by the Canadian Institutes of Health Research (CIHR, Grant No. MOP 133721), the Natural Sciences and Engineering Research Council of Canada (NSERC, Grant No. 418578‐2012 RGPIN) and the Craig. H. Neilsen Foundation (CHN, Grant No. 316495). A.A. is supported by Research Manitoba and the University of Manitoba.

Biographies

Arsalan Alizadeh is a PhD student in Soheila Karimi's Spinal Cord Injury and Stem Cell Laboratory at the University of Manitoba. Using primary glial cultures and in vivo models of spinal cord injury (SCI), his research projects aim to elucidate the role and potential of neuregulin‐1 therapy in regulating astrogliosis, neuroinflammation, myelin regeneration and functional recovery following SCI.

Soheila Karimi‐Abdolrezaee is a neurobiologist at the University of Manitoba with prime expertise in SCI and neural stem cell therapy. Her laboratory focuses on developing cellular and pharmacological approaches to promote remyelination and functional recovery following SCI and demyelinating conditions. Soheila Karimi received her PhD degree in developmental neurobiology with David Schreyer at the University of Saskatchewan. She then undertook a postdoctoral fellowship in spinal cord injury with Michael Fehlings at the Toronto Western Research Institute before establishing her own programme at the University of Manitoba in 2010.