Effect of glial cells on remyelination after spinal cord injury

Jai-feng wang, Xing-kai Liu, Rui Li, Ping Zhang, Ze Chu, Chun-li wang, Jua-rui Liu, Jun Qi, Guo-yue Lv, Guang-yi wang,Bin Liu, Yan Li, Yuan-yi wang

1 Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin Province, China

2 Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China

3 Hand & Foot Surgery and Reparative & Reconstruction Surgery Center, Second Hospital of Jilin University, Changchun, Jilin Province, China

4 Department of Emergency, First Hospital of Jilin University, Changchun, Jilin Province, China

5 Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin Province, China

6 Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA

7 Department of Orthopedics, First Hospital of Jilin University, Changchun, Jilin Province, China

How to cite this article: Wang HF, Liu XK, Li R, Zhang P, Chu Z, Wang CL, Liu HR, Qi J, Lv GY, Wang GY, Liu B, Li Y, Wang YY (2017)Effect of glial cells on remyelination aer spinal cord injury. Neural Regen Res 12(10):1724-1732.

Funding: is work was supported by the National Natural Science Foundation of China, No. 81601957.

Effect of glial cells on remyelination after spinal cord injury

Jai-feng wang1, Xing-kai Liu2, Rui Li3, Ping Zhang2, Ze Chu4, Chun-li wang2, Jua-rui Liu2, Jun Qi2, Guo-yue Lv2, Guang-yi wang2,Bin Liu5,＊,#, Yan Li6, Yuan-yi wang7,＊,#

1 Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin Province, China

2 Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China

3 Hand & Foot Surgery and Reparative & Reconstruction Surgery Center, Second Hospital of Jilin University, Changchun, Jilin Province, China

4 Department of Emergency, First Hospital of Jilin University, Changchun, Jilin Province, China

5 Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin Province, China

6 Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA

7 Department of Orthopedics, First Hospital of Jilin University, Changchun, Jilin Province, China

How to cite this article: Wang HF, Liu XK, Li R, Zhang P, Chu Z, Wang CL, Liu HR, Qi J, Lv GY, Wang GY, Liu B, Li Y, Wang YY (2017)Effect of glial cells on remyelination aer spinal cord injury. Neural Regen Res 12(10):1724-1732.

Remyelination plays a key role in functional recovery of axons aer spinal cord injury. Glial cells are the most abundant cells in the central nervous system. When spinal cord injury occurs, many glial cells at the lesion site are immediately activated, and different cells differentially affect inflammatory reactions aer injury. In this review, we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process. Activated astrocytes influence proliferation, differentiation, and maturation of oligodendrocyte precursor cells, while activated microglia alter remyelination by regulating the inflammatory reaction aer spinal cord injury. Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination aer spinal cord injury.

nerve regeneration; spinal cord injury; remyelination; oligodendrocyte precursor cells; astrocytes;oligodendrocytes; microglia; glial scar; demyelination; myelin; central nervous system; neural regeneration

Introduction

Spinal cord injury (SCI) is common and involves widespread damage to the central nervous system (CNS). SCI often leads to severe neurological symptoms such as varying degree of paralysis, paresthesia, urinary obstruction, and other progressive neurological abnormalities. SCI also involves social loss: data on western countries show that governments spend $40,000–$180,000 for each patient depending on the site of injury. Patients lose their jobs and receive medical treatment, rehabilitation, and maintenance, and each patient costs the country millions of dollars (Ning et al., 2012). In the 1920s, SCI cases increased from 6.7 to 60 per million in some regions of China (Ning et al., 2012).

The pathological process of SCI can be divided into two stages: primary injury and secondary injury. Primary injury occurs immediately aer the initial injury, and its pathological processes include demyelination of the spinal cord and necrosis of neurons and axons (Yu et al., 2016). Secondary injury occurs throughout the disease, and its pathological processes include demyelination, axonal and neuronal necrosis, nervous tissue ischemia and edema, oxidative stress,inflammatory reaction, and glial scar formation (Balentine,1978; Kwo et al., 1989; Wrathall et al., 1996; Azbill et al., 1997;Ray et al., 2016). Among these pathological reactions, demyelination occurs immediately aer injury, and is induced by oligodendrocyte necrosis after mechanical damage. At the stage of secondary injury, because of extensive apoptosis and autophagy of oligodendrocytes, axons that have not been damaged or are slightly damaged become necrotic owing to demyelination (Almad et al., 2011).

Myelin can be regenerated. When demyelinating lesions occur, newly generated oligodendrocytes can repair or reconstruct damaged myelin. Regeneration of myelin, with oligodendrocyte generation as the main physiological process, can last up to three months aer SCI. A recent study found that most oligodendrocytes required for remyelination aer demyelination are derived from oligodendrocyte precursor cells (OPCs) and neural progenitor cells. OPCs can be labeled by neural/glial antigen 2 (NG2) or platelet-derived growth factor (PDGF) receptor alpha, and show very active proliferation in the CNS (Alizadeh et al., 2015).Previously, OPCs were discovered to have a role in repairing myelin (Hackett and Lee, 2016). Moreover, OPCs have been called the fourth glial cells, in addition to astrocytes,microglia, and oligodendrocytes. OPCs become mature oligodendrocytes through migration, proliferation, differentiation, and maturation, and subsequently repair injured myelin. Nevertheless, the amount of new myelin is unable to cover all exposed axons, and the remyelination rate cannot keep up with the speed of demyelination. A negative myelin balance increases the number of naked axons, and thereby results in disability, degeneration, and sensory and motor disorders in residual nerves. In the CNS, the interaction between various glial cells and neurons is consistently demonstrated. Further, many of the physiological and pathological responses are strongly associated with intercellular biological signaling pathways. Increasing evidence shows that cellular interactions play a significant role in demyelination and remyelination (Domingues et al., 2016). After central nerve injury, various glial cells directly or indirectly damage myelin. Simultaneously, these glial cells also affect myelin regeneration. Here, the aim of this review is to summarize latest research results and discuss the effect of glial cells on remyelination in nervous tissue aer SCI.

Myelin and Demyelination

Myelin is composed of cytoplasm and the membrane of oligodendrocytes and Schwann cells. Myelin wraps around axons forming a special sheath-like structure. In the nervous system, the resistance of myelin is high, which reduces the capacitance of ensheathed axons. Consequently, myelin provides the structural basis for saltatory conduction of nerve signals (Nave and Werner, 2014). Myelin also provides nutritional support for ensheathed axons (Li and Leung, 2015).Only CNS oligodendrocytes generate myelin. Moreover,oligodendrocytes are associated with nerve signal transduction. A previous study suggested that myelin damage leads to abnormal neurological behavior (Love, 2006). Demyelination occurs immediately aer SCI.e mechanism of demyelination remains unclear, but one likely reason is death of oligodendrocytes induced by various factors (Nave and Trapp, 2008).ese factors include tumor necrosis factor-alpha- and interleukin-1 beta-mediated inflammatory reactions, glucose–adenosine triphosphate-mediated cytotoxicity, edema, and various free radical-induced ischemia/reperfusion injury (Almad et al., 2011; Plemel et al., 2014). A previous study demonstrated that a single oligodendrocyte can be involved with 30–80 axons, with each connection wrapping into an internode (O’Rourke et al., 2014). Thus,accidental death of each oligodendrocyte can cause a series of demyelination (Chong et al., 2012; Young et al., 2013).Physiologically, there is a special signaling pathway between myelin and the axon, with one reason for demyelination being that the axon–oligodendrocyte signaling pathway is damaged after axonal injury (Alizadeh et al., 2015). In the absence of axonal nutritional support, oligodendrocyte degeneration rapidly occurs, resulting in demyelinating lesions(Lappe-Siee et al., 2003).

OPCs and Remyelination

OPCs are small cells of bipolar or tripolar structure, which can be found in the white and gray matter of the CNS.e number of OPCs is greater in the white matter than gray matter (Dawson et al., 2003; Dincman et al., 2012). As precursor cells, a new view of OPC outcome has recently been developed from in vivo and in vivo studies. Purified rat OPCs can dedifferentiate into neural stem cells and then differentiate into neurons, oligodendrocytes, and type I and II astrocytes (Kondo and Raff, 2000; Belachew et al., 2003;Nunes et al., 2003). In contrast, Tognatta et al. (2017) meticulously labeled differentiating OPCs in mice with 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP)-Cre, but obtained insufficient evidence of OPC differentiation to neurons. OPCs can be specifically labeled by PDGF receptor alpha and NG2 proteoglycans (Tripathi and McTigue, 2007; Barnabe-Heider et al., 2010). OPCs can directly differentiate into oligodendrocytes without cell division (Hughes et al., 2013), but do not express NG2 aer differentiating into oligodendrocytes.

Nevertheless, the quality and integrity of regenerated myelin cannot meet demands owing to environmental change aer injury (Alizadeh et al., 2015). In the microenvironment after SCI, degenerative myelin secretes many inhibitory molecules. Simultaneously, the extracellular matrix, glial cell proliferation, and downregulation of nutrients and growthfactors affect remyelination (Meletis et al., 2008; Gauthier et al., 2013; Lukovic et al., 2015). The extracellular matrix can inhibit remyelination by blocking OPC migration (Siebert et al., 2011). Interleukin-beta limits OPC recruitment by activating the interleukin-1 receptor type 1 pathway(Kuroiwa et al., 2014).e glial scar produced by glial cells not only hinders OPC migration, but also results in a microenvironment that is not suitable for OPC proliferation.Degenerative myelin activates multiple microglial signaling pathways leading to release of inflammatory mediators (Sun et al., 2010). These molecules and cytokines inhibit axonal regeneration and destroy myelin integrity through the complement system (Chen et al., 2000).

Table 1 Factors known that regulate remyelination via different effects on OPCs

In summary, there are several reasons for lack of remyelination: (1) the remyelination process lacks the necessary growth factors for promoting formation of intact mature myelin from newborn oligodendrocytes; or (2) there is death of newborn OPCs as there are not enough biochemical factors to promote production of related cells and myelin.Consequently, the microenvironment at the injured site after SCI has an inhibitory effect on remyelination. In view of this, OPCs should be at the core of studies on remyelination,relieving inhibition, and promoting proliferation and differentiation of OPCs.

Recently, increasing research has focused on promoting remyelination by improving OPC migration, proliferation,differentiation, and maturation after SCI. Many drugs,hormones, and even treatments have been used clinically and are shown to be effective (Table 1). A previous study reported that as a hormone, progesterone improves OPC survival rate at the injury site by mitigating the inflammatory response and improving reactive gliosis after SCI(Huang et al., 2015). The Chinese herbal medicine, dried tangerine peel, can improve remyelination by increasing bone morphogenetic protein (BMP) 2.5 expression and elevating Ddx54 expression in cerebral ventricles, the subventricular zone, and corpus callosum (Tokunaga et al.,2016). Amiloride is a potassium-conserving diuretic that has been shown to promote remyelination by reducing the endoplasmic reticulum stress response and reducing OPC apoptosis (Kuroiwa et al., 2014). In addition to these drugs,there is evidence that physical therapy also has a role in promoting remyelination. Huang et al. (2015) reported that electroacupuncture promotes OPC proliferation, reduces OPC death, and improves remyelination. There have also been breakthroughs in promoting remyelination by overexpressing certain molecules in OPCs. Yao et al. (2017) reported that PGDF-AA-overexpressing OPC transplantation in rats induces remyelination. Myelin regulatory factor (MRF)overexpression was also reported to stimulate OPC differentiation (Xie et al., 2016). Although the mechanism of remyelination is not fully understood, there are numerous ways to promote remyelination. Most of these methods are supported by compelling evidence, but there is still considerable distance between these factors and clinical applications, and a need for continued innovation.

Astrocytes and Remyelination

Astrocytes are widely present in the CNS. They are the most abundant glial cells in white matter and gray matter,and have a crucial role in neurophysiology. A recent study demonstrated that two kinds of astrocytes in brain tissue: fibrous astrocytes in the white matter of the corpus callosum,and protoplasmic astrocytes in the gray matter (Ding, 2014).e primary function of astrocytes was initially thought to support and supply neurons, but nowadays there is plenty of evidence showing that astrocytes are strongly associated with microglia, oligodendrocytes, and other astrocytes in the nervous system. Astrocytes regulate neurotransmitters, participate in synaptogenesis, mediate the immune response, express extracellular matrix molecules, promote cell migration, and promote differentiation and maturation of the CNS (Walz, 1989; Westergaard et al., 1995; Sofroniew and Vinters, 2010; Clarke and Barres, 2013). Astrocytes are associated with many pathological CNS processes, including inflammation, ischemia, infection, and degeneration. Aer activation, changes in cell morphology, gene expression, and cell physiology are observed in astrocytes (Sofroniew and Vinters, 2010). A previous study confirmed that astrocytes directly affect proliferation and survival of the oligodendrocyte line (Li et al., 2016), demonstrating that oligodendrocytes are strongly associated with remyelination. Astrocytes are involved in regulating the balance between Schwann cells and oligodendrocyte remyelination, with oligodendrocyte remyelination only observed in areas where astrocytes are present. A recent study showed that testosterone promoted oligodendrocyte remyelination via astrocyte recruitment(Bielecki et al., 2016). Indeed, increasing evidence shows that astrocytes directly or indirectly affect remyelination by acting on OPCs or oligodendrocytes (Figure 1).

Figure 2 Microglia and remyelination.

Figure 1 Astrocytes affect remyelination by affecting OPC differentiation and maturation or directly acting on oligodendrocytes.

OPCs and astrocytes are homologous during development, and OPCs can directly differentiate into astrocytes in vitro (Raff et al., 1983). Furthermore, an in vivo study found that immature astrocytes are present within NG2+cells aer SCI (Lytle et al., 2009). While another study confirmed that after SCI, OPCs that differentiate into oligodendrocytes are limited. Further, some OPCs (4–13%) do not differentiate into oligodendrocytes, and instead differentiate into astrocytes (Sozmen et al., 2016). OPC differentiation into astrocytes will affect remyelination. BMP and Olig2 may be involved in differentiation of OPCs into astrocytes. Regarding BMP, current understanding is that BMP4 increases aer SCI, with its potential source being reactive astrocytes aer injury (Wang et al., 2011). BMP4 contributes to OPC differentiation into astrocytes, although BMP4 antagonists have only a limited inhibitory effect on differentiation into astrocytes (Hampton et al., 2007). Olig2 may inhibit OPC differentiation into astrocytes: Olig2 overexpression reduces differentiation of neural stem cells into astrocytes in vitro(Fukuda et al., 2004). During development, a large number of Olig2 knockout OPCs differentiate into astrocytes instead of myelin (Zhu et al., 2012). Reticulon 4 receptor (NgR1) is a Nogo receptor that can suppress OPC differentiation into oligodendrocytes. Its antagonist promotes OPC differentiation into mature oligodendrocytes (Hampton et al., 2007;Sozmen et al., 2016). Molecules that promote OPC differentiation into astrocytes also include hyaluronan, janus kinase(JAK)-Stat1, and jagged-1 (Back et al., 2005; Zhang et al.,2009). In addition, inhibition of leucine rich repeat and Ig domain containing 1 (LINGO-1) promotes OPC differentiation into mature oligodendrocytes, and LINGO-1 inhibitors have been used for treatment of multiple sclerosis (Mi et al.,2013). In conclusion, OPC differentiation into astrocytes and oligodendrocytes ensures remyelination is a fluctuating process. Specifically, excessive OPC differentiation into astrocytes reduces the number of mature oligodendrocytes.Astrocytes have a significant inhibitory effect on remyelination and axonal regeneration.us, recovery of neurological function worsens aer SCI. Inhibition of astrocyte differentiation contributes to remyelination and ensures recovery of neurological function aer SCI.

Activated astrocytes lead to specific reactive gliosis. During this process, their morphology changes significantly and a large amount of intermediate filament proteins, mainly glial fibrillary acidic protein (GFAP) and nestin, are secreted to form the glial scar (Karimi-Abdolrezaee and Billakanti,2012). There are two sources of activated astrocytes after SCI: (1) ependymal cell GFAP-astrocytes; and (2) in situ activated GFAP+astrocytes.ey play different roles in glial scar formation (Meletis et al., 2008; Barnabe-Heider et al.,2010). Activated astrocytes are harmful to remyelination and involved in scar tissue formation, inhibition of OPC migration, survival and differentiation aer SCI, and even axonal regeneration (Wang et al., 2011). As a type of immunocyte in the CNS, astrocytes express many protein kinases, glycoproteins, and chondroitin sulfate proteoglycans aer activation.ese molecules induce inflammatory responses and the glial scar directly or indirectly causes severe damage to oligodendrocytes and neurons, chemically or physically (Silver and Miller, 2004). Glial scar formation limits the inflammatory reaction around the injury site, isolates damaged nerve tissue from normal tissue, and plays a supporting role in injured tissue. Simultaneously, the glial scar has a negative effect on remyelination and axonal regeneration. When axonal regeneration is inhibited, the link between axon and myelin is destroyed, and remyelination is not possible. Transplantation of OPCs and neural precursor cells into the injury site at the subacute stage contributes to axon myelination, but does not achieve a good outcome.is indicates that the internal environment aer injury around the glial scar has an inhibitory effect on remyelination or myelination of axons (Keirstead et al., 2005; Karimi-Abdolrezaee et al., 2006). Activated astrocytes secrete a variety of chondroitin sulfate proteoglycans,mainly consisting of neuroncan and brevican, and versican in the nervous system (Yamada et al., 1994).ey all have an inhibitory effect on remyelination and axonal regeneration(Dyck and Karimi-Abdolrezaee, 2015). Activated astrocytes affect OPC recruitment and maturation, and axonal ensheathment by secreting chondroitin sulfate proteoglycans,and finally inhibiting remyelination (Dyck and Karimi-Abdolrezaee, 2015). Chondroitin sulfate proteoglycans not only affect OPCs, but Karimi-Abdolezaee et al. (2010) found that chondroitin sulfate proteoglycans and the glial scar affect differentiation of neural precursor cells to oligodendrocytes.e glial scar is not only composed of astrocytes and microglia, and reactive activated OPCs are also involved in scar formation. OPCs also express chondroitin sulfate proteoglycans to inhibit axonal regeneration and repair myelin (Chen et al.,2002). Another inhibitory molecule secreted by astrocytes is hyaluronan, which is extensively found in the extracellular matrix and white matter of the CNS (Sherman et al., 2002).Hyaluronan can act on CD44 receptors of T cells and OPCs,and affect OPC maturation (Back et al., 2005; Lundgaard et al., 2014).

Reactive activated astrocytes aer SCI participate in glial scar formation. Changes in their own cell products and the microenvironment surrounding glial scars have a strong inhibitory effect on remyelination (Wang et al., 2015). Some inflammatory factors mitigate scar formation in reactive gliosis by inhibiting astrocyte activation, which may be a way to improve remyelination aer SCI. Wang et al. (2015)suggested that blocking the signaling pathway of platelet activating factor can reduce reactive gliosis and inhibit demyelination after SCI. Ishii et al. (2016) found that the RAS-related C3 botulinum substrate 1 (Rac1)–G1 to S phase transition 1 (GSPT1) signaling pathway is a new axis for regulating gliosis aer SCI.ese studies provide evidence for remyelination aer SCI.

Microglia and Remyelination

Microglia are macrophages present in the nervous system,and are involved in cellular immunity of the nervous system.Microglia are usually in a resting state, and in this state are in a “cruising” state to detect a pathological reaction at any time (Hanisch and Kettenmann, 2007). When a “crisis” arises, microglia can be immediately activated from the resting state, migrate to the injury site, and participate in formation of the outer layer of the glial scar to isolate damaged tissue from normal tissue (Davalos et al., 2005). Nevertheless,excessively activated microglia secrete large amounts of inflammatory factors, cytotoxic agents, and free radicals,thereby causing a severe inflammatory response, which undoubtedly inhibits remyelination. However, in recent years,more and more studies have focused on promoting the effect of microglia on remyelination. Microglia can be divided into different subtypes in the CNS, which play distinct roles in remyelination (Figure 2).

Microglia have an important effect on remyelination.With demyelinating lesions following SCI, some myelin fragments may remain outside residual axons. If these residual myelin fragments cannot be removed, they will have an impact on new myelin. Microglia are responsible for removal of fragments (Kotter et al., 2006; Neumann et al., 2009).Both in vivo and in vivo, these residual fragments can influence differentiation, maturation, and myelination of OPCs(Nave, 2010). A previous study reported that this microglial function is dependent on downstream activation of the DAP12 signaling pathway by triggering receptor expressed on myeloid cells 2 (TREM2) (Poliani et al., 2015). A residual amount of these fragments is associated with phagocytic function of microglia/macrophages. Moreover, this function is largely determined by the age of the organism. If the blood of young animals is injected into the body of older animals, remyelination of older animals is improved (Miron and Franklin, 2014). Astrocytes recruit microglia to the site of injury by expressing the chemokine, CXCL10, which enhances phagocytosis of myelin fragments. If astrocytes are removed from the culture medium, removal of myelin fragments can be affected, resulting in inhibition of proliferation and myelination of OPCs (Skripuletz et al., 2013). Receptors associated with microglial phagocytosis of myelin fragments include CR3, SRA, and Fc gamma. A previous study found that CR3 can reduce phagocytosis by activating or downregulating microglial phagocytosis to act on phosphorylated cofilin via the spleen tyrosine kinase (Syk) signaling pathway(Hadas et al., 2012). Simultaneously, CR3 and SRA interact to mediate phagocytosis following axonal injury (Makranz et al., 2004). Expression of galectin-3/MAC-2 can alter phagocytosis of microglia by modulating CR3 and SRA (Rotshenker et al., 2008).e TLR4 agonist, E6020, promotes repair of damaged myelin by stimulating microglia phagocytosis and myelinating cell recruitment (Church et al., 2017). It also blocks the TLR4 signaling pathway leading to delayed phagocytosis and altered expression of cytokines such as insulin-like growth factor-1, fibroblast growth factor-2, and interleukin-1 beta, which ultimately reduces remyelination aer SCI (Church et al., 2016).

Macrophages/microglia secrete a variety of cytokines,chemokines, and growth factors to affect remyelination aer SCI. Microglia are divided into two subtypes, namely,M1 cells involved in the inflammatory response and M2 cells with anti-inflammatory and repair effects (Kigerl et al.,2009). M1 cells are strongly associated with the inflammatory response and suppress remyelination. M2 cells are classified into three subtypes: M2a, M2b, and M2c (Gensel and Zhang, 2015). Kigerl et al. (2009) found that M2 microglia ameliorate chondroitin sulfate proteoglycan-induced axonal degeneration and reduce residual myelin fragments. M2 microglia gradually occupy a dominant activated microglial position at 3–10 days aer demyelination.is time window coincides with OPC recruitment and differentiation into mature oligodendrocytes at the site of injury (Miron et al.,2013). A further study verified that M2a and M2c microglia promote differentiation and maturation of oligodendrocytes by selectively removing M2 microglia (Miron and Franklin,2014).ese above studies confirm that M1 microglia inhibit remyelination aer SCI. M2a and M2c (suspected) microglia may promote remyelination by promoting recruitment,proliferation, differentiation, and maturation of OPCs aer SCI. Interleukin-10 is secreted by M2b microglia and an anti-inflammatory cytokine. Aer SCI, with activation of M2a cells, M2b cells reach a peak at 4–5 days aer injury. Another study demonstrated that M2b cells protect against axonal degeneration. Although it is not clear if M2b cells have a direct effect on remyelination, there is enough evidence to show that M2b and M2c cells promote spinal cord tissue repair by modulating cell proliferation (including OPCs) at the proliferative stage aer SCI (Gensel and Zhang, 2015). Bartus et al.(2014) have found that lentiviral introduction of the ChABC gene immediately aer SCI promotes a neuroprotective form of M2 microglia and increases storage of neurons and axons after 12 weeks of SCI. They also reported that this effect of ChABC may be produced by increasing expression of the anti-inflammatory factor, interleukin-10, and reducing the inflammatory factor, interleukin-12 beta (Didangelos et al.,2014). To date, increasing pathways have been shown to shiM1/M2 polarization.e amount of M1/M2 polarization is associated with age, with more M1 polarization detected in infarcted brain from older stroke models and more M2 labels found in younger ones (Suenaga et al., 2015). Also, many mediators (such as interleukin-4 and -13) can enhance M2 polarization (Wang et al., 2014; Roszer, 2015). Wang et al.(2017) reported that heterochromatin protein 1c (HP-1c)activates the 5′AMP-activated protein kinase (AMPK)-Nrf2 pathway to alter M1/M2 polarization and reduce the inflammatory reaction in stroke models. Cocoa polyphenolic extract is reported to shiM1/M2 polarization, in which M1 polarization is reduced and alternatively, M2 polarization induced (Dugo et al., 2017). Although quite a few pathways are related to M1/M2 polarization, and many molecules have shown their anti-inflammatory potential by reducing/inducing M1/M2 polarization, alteration of M1/M2 polarization aer SCI has yet to be fully understood.

Besides astrocytes, microglia are also associated with the iron supply chain in the nervous system. Increasing iron content in microglia increases the survival rate of co-cultured OPCs, verifying that microglia are a source of iron in OPCs (Zhang et al., 2006). Considering a similar role of astrocytes, microglia may improve iron protein content in both types of glial cells after SCI, improve iron supply in OPC–oligodendrocyte lines, and be helpful for remyelination aer injury.

Summary

With an increasing number of SCI patients, the study of demyelination/remyelination aer SCI has become increasingly significant. In addition to neurons, glial cells are resident cells in the CNS. Glial cells play supporting, nutritional, and immunological roles in the CNS. Simultaneously, glial cells are intimately associated with each other. Aer SCI, various signaling pathways are initiated, which can activate/injure glial cells and induce an inflammatory response, glial scar formation, neuronal injury, necrosis, and demyelination.In demyelinating lesions, OPCs in nerves replace lost oligodendrocytes and become new myelin via migration, proliferation, differentiation, and maturation. However, aer glial cell activation, the surrounding environment is changed and OPC myelination is affected by many factors. Astrocytes are the most abundant glial cells in the CNS.ey secrete chon-droitin sulfate proteoglycans after activation. Astrocytes also induce glial scar formation, which has a large effect on remyelination. Microglia as major immune cells of the CNS initiate an inflammatory response aer injury. Inflammatory cytokines expressed in microglia affect remyelination. M2 microglia promote OPC proliferation, differentiation, and maturation. Taken together, controlling reactive activation of glial cells after SCI to improve remyelination is an important approach to treat injured spinal cord and promote recovery of neurological function.

Author contributions:HFW conceived the manuscript. XKL, PZ, ZC,HRL and JQ collected data. YL searched bibliography. RL organized figures and table. YYW draed and revised the paper. BL wrote the paper.GYL and GYW revised the paper. All authors approved the final version of the paper.

Conflicts of interest: None declared.

Data sharing statement:Datasets analyzed during the current study are available from the corresponding author on reasonable request.

Plagiarism check: Checked twice by ienticate.

Peer review:Externally peer reviewed.

Open access statement:is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under identical terms.

Open peer reviewer:Na Lin, Kunming Medical University, Basic Medical Sciences, China.

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＊Correspondence to:

Yuan-yi Wang, M.D. or Bin Liu, M.D.,tedwangyy@foxmail.com or 1466802342@qq.com,359382923@qq.com.

orcid:

0000-0002-6163-5144

(Yuan-yi Wang)

0000-0007-7182-8644

(Bin Liu)

10.4103/1673-5374.217354

Accepted: 2017-09-14

Copyedited by James R, Frenchman B, Wang J, Li CH, Qiu Y, Song LP,Zhao M