stem cell for the treatment of neuropathic pain...stem cell trans-plantation may be an important...

Journal of Anesthesia and Perioperative Medicine

This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed un-der the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution,and reproduction in any medium or format for any lawful purpose.To view a copy of this license, visit http://cre-ativecommons.org/licenses/by/4.0/.

From 1Department of Anesthesiolo-gy, Beijing Chaoyang Hospital, CapitalMedical University, Beijing, China;2Department of Anesthesiology, Bei-jing Anzhen Hospital, Capital MedicalUniversity, Beijing, China; 3Depart-ment of Anesthesiology and CriticalCare Medicine, Johns Hopkins Univer-sity School of Medicine, Baltimore,Maryland, USA.

Correspondence to Dr. Yun Wang [email protected].

Citation: Fang Xie, Yun Yue, YunGuan. Stem cells for the treatmentof neuropathic pain. J Anesth Periop-er Med 2017; x: x-x.

Aim of review: Neuropathic pain induced by injury to the somatosensory system is agreat clinical problem. Despite multiple therapeutic strategies, the medical communi-ty still faces a challenge to treat neuropathic pain in a complete and definitive way,since the pathogenesis of this hypersensitive state is very complex. Stem cell trans-plantation may be an important approach for the treatment of neuropathic pain. Thisarticle aimed to review important and illustrative results from recent stem cell studiesunder various neuropathic pain conditions and to interpret their clinical implicationsfor stem cell transplantation.Method: We reviewed recent articles and literatures about stem cells for the treat-ment of neuropathic pain, in order to identify the types of stem cells, delivery ap-proaches and the advances of stem cells for the treatment of peripheral nerve injuryinduced neuropathic pain, painful diabetic peripheral neuropathy and spinal cord in-jury (SCI) induced chronic pain.Recent findings: Recently, the successful use of stem cell for the treatment of a di-verse spectrum of diseases in animals has attracted more attentions from pain scien-tists. Accumulating evidence has shown that stem cell transplantation has a therapeu-tic effect on neuropathic pain. Stem cell transplantation can effectively relieve neuro-pathic pain under different pathological conditions. However, it is interesting topoint out that peripheral neuropathic pain seems to be more responsive to stem celltherapy than SCI- induced chronic pain. Moreover, stem cell treatment does not al-ways exert positive results in SCI- induced chronic pain (e.g. aggravating pain abovethe lesion spinal cord segment).Summary: The analgesic effect of stem cells depends on the capacity to offer a multi-potent cellular source for replacing injured neural cells and delivering trophic factorsto lesion sites. Stem cell researches should focus on both experimental and clinicalstudies of neuropathic pain in the future.

ABSTRACT

Neuropathic pain triggered by mul-tiple insults to the somatosensorysystem is a clinical problem and

the pathogenesis of this hypersensitivestate is very complex, involving structur-al and neurophysiological changes. Cur-rently, there are no drugs that can treatneuropathic pain in a complete and de-finitive way. Therefore, there is an over-whelming need to develop a novel drugor approach for the treatment of neuro-

pathic pain. Recently, stem cells trans-plantation has been recognized as an im-portant approach for the treatment of avariety of diseases in the future. Neuro-scientists have also been beginning to re-alize the potential application of stemcells for the treatment of neuropathicpain. This review will characterize thetypes of stem cells, delivery approaches,and highlight the recent advances ofstem cells for the treatment of various

Stem Cells for the Treatment of Neuropathic PainFang Xie1,2, Yun Yue1, Yun Guan3, and Yun Wang1

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JAPM WWW.JAPMNET.COM x, 2017 Volume x Number x

neuropathic pain states.

Types of Stem Cells for the Treatment of ChronicPain

Stem cells are defined as cells that possess thepotential of self- replication and multipotent dif-ferentiation. According to the stage of develop-ment, they are classified as embryonic stem cellsand adult stem cells. Because embryonic stemcell researches have some ethical limitations,adult stem cells such as neural stem cells(NSCs), mesenchymal stem cells (MSCs) andbone marrow mononuclear cells (BM- MNCs)are more widely used in experimental and clini-cal studies. NSCs present in the hippocampaldentate gyrus, olfactory bulb, subventricularzone (SVZ) surrounding the ventricles, subcallo-sal zone underlying the corpus callosum, andthe spinal cord of the embryonic, neonatal, andadult rodent central nervous system (CNS) (1),as well as human fetal CNS (2). Under particu-lar conditions, they can differentiate into neu-rons, astrocytes and oligodendrocytes (3). Themost commonly used cells for pain relief areMSCs such as those from bone marrow (bonemarrow MSC, BMSC) and adipose tissues (adi-pose tissue derived MSC, ASCs), excluding he-matopoietic cells. Moreover, BM-MNCs have al-so been extensively evaluated for the treatmentof chronic pain. They are bone marrow-derivedcells which contain various kinds of cell lineages(e.g., hematopoietic cells, fibroblasts, osteo-blasts, myogenic cells and endothelial lineage)(4). In addition, endothelial progenitor cells(EPCs) are progenitor cells of mature endotheli-al cells that show potential for their endothelialrepair and vasculogenesis. They are being ex-plored as therapeutic cell types for chronic isch-emic pain, especially painful diabetic peripheralneuropathy. Recently, the therapeutic effects ofhuman umbilical cord blood- derived mesenchy-mal stem cells (hUCB- MSCs) and amniotic epi-thelial stem cells (hAESCs) on chronic pain at-tract researchers' attention. HUCB-MSCs are de-rived from the umbilical vessels (i.e., two umbili-cal arteries and one umbilical vein) which areembedded in Wharton's jelly (WJ); hAESCs arederived from amniotic epithelium. They haveemerged as alternative cell types for attractive

advantages such as low risk of infection and tera-toma formation, multipotency and low immuno-genicity (5).

Multiple Approaches for Stem Cells Delivery inthe Treatment of Neuropathic Pain

Stem cells can be transplanted by local delivery,intrathecal or intracerebroventricular administra-tion, intravenous injection, intranasal deliveryand endogenous mobilization by drugs forchronic intractable pain treatment. Hofstetter etal. (6) performed local delivery of neurogenin-2expressing- NSCs directly into the damaged spi-nal segments in rats subjected to spinal cord inju-ry, and found that it could reduce allodynia andimprove motor function. However, the trans-plantation manner has some disadvantages suchas local bleeding and tissue injury, which restrictits use (7). Hence, intravenous injection is moreattractive for clinical application given thebroad distribution. Surprisingly, following intra-venous administration, stem cells can migratefrom blood vessels into the central nervous sys-tem, crossing the blood-brain barrier (8-10), andmight therefore home and integrate themselvesinto the DRG and spinal cord dorsal horn. Ithas been demonstrated that human BMSC ei-ther injected in the mouse lateral cerebral ventri-cle (11) or systemically into the caudal vein (12)were able to home into the spinal cord and pre-frontal cortex of SNI- induced neuropathic miceto repair the damage. Another animal study ofchronic constriction injury (CCI) models in ratshas also shown that stem cells have a capacity ofspecifically reaching the damaged nerve (13) af-ter a systemic injection to exert an analgesic ef-fect. However, systemic delivery has a pulmo-nary trapping effect and only a few cells canreach the injured sites (7), which restrict its clini-cal application. Intrathecal administration is acommon drug- given approachof pain research.The intrathecal administration of stem cells al-lows the target for DRGs and spinal cord in thepain pathway and helps to clarify the underlyingmechanisms (14). Recently, intranasal delivery isemerging as a noninvasive option for deliveringstem cells with minimal peripheral exposure(15). Finally, the endogenous stem cells in thebone marrow might be mobilized by drugs (e.g.,

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Stem Cells and Neuropathic PainFang Xie et al.

granulocyte-colony stimulating factor and plerix-afor) into the blood flow, therefore home to thelesion sites (16, 17).

Peripheral Nerve Injury- Induced NeuropathicPain

Neuropathic pain induced by peripheral nerveinjury is challenging to treat and often refracto-ry to current pharmacotherapies. Despite de-cades of research, information regarding themechanism of peripheral neuropathic pain issparse. However, in recent years, some studieshave suggested that the uninjured fibers inter-mingled with degenerating injured nerve fibersplay critical roles in peripheral nerve injury- in-duced neuropathic pain (18). It is well estab-lished that nerve damage leads to Wallerian de-generation which causes the formation of neuri-nomas and alteration of nerve conduction (19)that result in neuropathic pain. In addition, dur-ing peripheral nerve injury, the adjacent unin-jured nerve fibers develop ectopic and spontane-ous discharges which are associated with centralsensitization in neuropathic pain development.Hence, providing a favorable milieu for the in-jured and adjacent uninjured nerve fibers mayease neuropathic pain. About providing a protec-tive microenvironment, neurotrophic factors areknown to induce neuroprotection by maintain-ing functional integrity, promoting regeneration,regulating neuronal plasticity, and repairing thedamaged nerves (20). Furthermore, recent stud-ies have demonstrated that the activation of im-mune system also contributes to peripheral neu-ropathic pain pathology (21). Immune cells canpenetrate into peripheral and central nervoussystem, activate glial cells and initiate a series ofneuroinflammatory cascade which are known tofacilitate pain signaling. In turn, the cascade ofneuroinflammation- related events may maintainand worsen the original lesions and subsequent-ly result in a more generalized immune response(22, 23). Consequently, protecting the injury mi-croenvironment and balancing the pro- and anti-inflammatory cytokines may open new avenuesfor neuropathic pain treatment.

Stem cells have been shown to release neuro-trophic and anti- neuroinflammatory cytokines.An interesting note is that stem cells, regardless

of their sources, can secrete neurotrophic fac-tors. For example, human mesenchymal stem/stromal cells (hMSCs) produce at least 84 tro-phic factors including epidermal growth factor(EGF), brain derived neurotrophic factor(BDNF), neurotrophin- 3 (NT- 3), ciliary neuro-trophic factor (CNTF), basic fibroblast growthfactor (bFGF/FGF- 2), hepatocyte growth factor(HGF), and vascular endothelial growth factor(VEGF) (24). Further, these neurotrophic fac-tors have also been released by ASCs and otherstem cells (25). Neurotrophic factors released bystem cells have neuroprotective and neuroregen-erative effects (26, 27). Additionally, both in vi-tro and in vivo studies have shown that stemcells can balance pro- and anti- inflammatory cy-tokines via paracrine effect (28). In vitro experi-ments, stem cells present an immunosuppressiveeffect by interacting with immune cells and regu-lating soluble factors such as cytokine interleu-kin-1β (IL-1β) and IL-10 (29, 30). Other studieshave shown that stem cells can inhibit the neuro-inflammatory cascade through bystander effectin vivo (12, 13, 31). Besides, other mechanismsof stem cells including opioids may also be in-volved in relieving peripheral nerve injury- in-duced neuropathic pain (32). Together, these da-ta clearly indicate that, stem cells can produceboth neurotrophic factors and neuromodulatorsfollowing administration and therefore exert ananalgesic effect.

Because stem cells of different origin all re-lease neurotrophic factors and neuromodula-tors, various kinds of stem cells exhibit therapeu-tic effect on peripheral neuropathic pain. Con-sidering the homologous development of the le-sion in the peripheral and central nervous sys-tem, NSCs seem to be the most appropriate celltype to prompt physiological repair of the le-sion. Xu et al. (33) considered that intrathecaladministration of NSCs significantly attenuatedmechanical and thermal hyperalgesia via markedincreasing protein and mRNA levels of glial cellline derived neurotrophic factor (GDNF) in thespinal dorsal horn and dorsal root ganglia ofnerve- injured rats. Yet, another experiment inrats subjected to neuropathic pain from CCIdemonstrated that the effect contributing toNSCs- induced pain relief depends upon the re-duction of proinflammatory cytokines (e.g., IL-1

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and IL-6) and the production of anti- inflamma-tory IL-10 mRNA (13). However, different injec-tion strategies may be responsible for the dis-tinct mechanisms. Recently, ASCs have emergedas an attractive cell type for the treatment ofchronic pain because it can be acquired by lowinvasive procedures. Like NSCs, by the use ofASCs isolated from female donors undergoingplastic surgery, recently published data showedthat intravenous administration of ASCs in-duced a rapid, long lasting and dose dependentantihyperalgesic and antiallodynic effect (31).Importantly, ASCs- induced thermal hyperalgesiaseems to be more potent and the level of anti-in-flammatory IL- 10 is higher compared to NSCstransplantation, suggesting that ASCs producean increased analgesia in response to peripheralnerve injury (18). Moreover, these studies alsoshowed that NSCs and ASCs both exert dose-de-pendent analgesia by repeated administration.Analogously, MSCs also offer a prominent celltype for the treatment of peripheral neuropathicpain as ASCs, because they have no marked phe-notypic differences. In neuropathic pain mice,Siniscalco et al. (12) reported that systemic ad-ministered hMSCs can permeate the blood-brainbarrier to home in the spinal cord and prefron-tal cortex, where they can reduce the proteinlevels of pro- inflammatory cytokines (i.e., IL-1βand IL-17) and increase protein levels of anti-in-flammatory cytokines (i.e., IL- 10) that partici-pate in pain formation. Besides, BM-MNCs, an-other type of stem cells from bone marrow, arebeginning to yield encouraging results. Klass etal. (34) reported the beneficial effect of BM-MNCs in attenuating neuropathic pain in a CCIrat model although the mechanisms were not in-volved. Together, these data suggest that the neu-rotrophic factor- releasing nature coupled withthe neuroinflammation regulatory capacity ofstem cells may contribute to the relief of periph-eral neuropathic pain. However, more extensiveresearches are still needed in this area to uncov-er the beneficial effects of stem cells before addi-tional clinical trials are conducted.

Painful Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is themost common complication of diabetes mellitus,

affecting up to 60% of diabetic patients (35).Symmetric spontaneous pain, hyperalgesia, allo-dynia and paresthesia are early symptoms ofDPN (36). Especially, painful diabetic peripheralneuropathy (pDPN) which presents in 3% toover 20% of diabetic patients (37) is often re-fractory to current pharmacotherapies. It is wellestablished that long- term diabetes leads to thedestruction of peripheral blood vessels, particu-larly the vasa nervorum, and this destructioncan cause microcirculation transformation andneurotrophin reduction in peripheral nervesthat result in pDPN (38). In addition, deficiencyof neurotrophic factors in the development andprogress of pDPN results in distal axonal degen-eration, axonal loss, and demyelination (39),which may attribute to the distal pre- dominantnerve pathology. Taken together, because themechanism involves both vascular and neuro-trophic deficiency, using a therapeutic agent thathas dual angioneurotrophic activities may provebeneficial for the treatment.

For many decades, most researches on stemcells have revolved around neurotrophic mecha-nism. However, recent studies have demonstrat-ed that stem cells also have paracrine propertiesof angiogenic cytokines. For example, EPCs pro-duce multiple angiogenic factors such as VEGF,insulin- like growth factor- 1 (IGF- 1), and fibro-blast growth factor- 2 (FGF- 2) (40); other stemcells (e.g., BM- MNCs and MSCs) have alsobeen shown to release angiogenic ligands (41,42). Angiogenic factors have been reported toplay a crucial role in neovascularization (43).Furthermore, most angiogenic factors releasedby stem cells also exert neurotrophic effects.Thus, stem cell transplantation may exhibit ther-apeutic effects encompassing both supplyingneurotrophic cytokines through direct effects onfunctional recovery of peripheral nerves and in-ducing neovascularization to crease nerve bloodflow. Different mechanisms of stem cell trans-plantation involved in different pathologicalconditions were shown in figure.

Application of stem cells in preclinical studiesand clinical trials for therapeutic purposes is be-ginning to yield encouraging results. EPCs areputative progenitor cells of endothelial cells thatcontribute to postnatal neovascularization. Forexample, cord blood-derived endothelial progen-

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itor cells (CB- EPCs) were reported to improvemotor nerve conduction velocity (MNCV) andsciatic nerve blood flow (SNBF) with intramus-cular injection in streptozotocin (STZ)- induced

diabetic rats through enhancing vascular densityin the treated leg muscles (44). Another mecha-nism by which EPCs contribute to pDPN is up-regulating the expression of mRNA and proteins

Figure. Different Mechanisms of Stem Cell Transplantation Involved in Different Pathological Conditions.The major analgesic mechanisms of stem cell transplantation under the conditions of peripheral nerve injury, painful peripheral dia-

betic neuropathy and spinal cord injury are now believed to be different and they can be divided into five main categories: immuno-

modulation, neurotrophic effect, biologic minipump, differentiation and angiogenesis. Although knowledge of stem cell- dependent

mechanisms known to mediate the relief of chronic pain increases every year, these mechanisms are depicted here for illustrative

purposes. The immunomodulatory effects of stem cells consist of inhibition of the pro-inflammatory cytokines (e.g., TNF-α, IL-1 and

IL-6) and upregulation of anti-inflammatory cytokines (e.g., IL-4, IL-10 and IL-13). Stem cells and stem cell-stimulated resident cells

also release neurotrophic factors (e.g., EGF, BDNF, GDNF, NT-3, bFGF and VFGF), which are responsible for neuroprotective and

neuroregenerative effects. Neurotrophic factors are acted through autocrine effect on differentiated cells and paracrine effect on resi-

dent neurons and glial cells. In addition, stem cells can be genetically modified and then transplanted as a biological minipump to re-

lease neurotransmitters and neurotrophins (e.g., γ-GABA, glycine, GDNF and neurogenin-2). Moreover, the special characteristics

of stem cells are associated with their differentiation into neuron, astrocyte, oligodendrocyte and microglia. Finally, stem cells stimu-

late local angiogenesis by secretion of extracellular matrix molecules, VEGF, IGF-1, FGF-2, PIGF and bFGF. However, after stem

cell transplantation, immunomodulation and neurotrophic effects are mainly responsible for peripheral nerve injury induced neuro-

pathic pain, neurotrophic effect and angiogenesis for painful peripheral diabetic neuropathy; and biologic mini-pump and differentia-

tion are primarily associated with spinal cord injury induced chronic pain. Meanwhile, these mechanisms may interact with each oth-

er under different pathological conditions.

Fang Xie et al. Stem Cells and Neuropathic Pain

Immunomodulation

Anti-inflammatory state

Pro-inflammatory state

Stem cells

Leukocytes infiltration

IL-4IL-10IL-13……

TNF-αIL-1IL-6……

Neurotrophic effect

Autocrine

Ne

rvere

ge

ne

ratio

n

Stem cells

EGFBDNFGDNFNT-3bFGFVEGF……

Paracrine

Spinal cord injury

Peripheral nerve injury

Painful peripheraldiabetic neuropathy

Biologic minipump Differentiation Angiogenesis

Stem cellsStem cellsStem cells

Transduction γ-GABAglycineGDNFneurogenin-2……

Neuron Astrocyte oligodendrocyte Microglia

VEGFIGF-1FGF-2PIGFbFGF……

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of VEGF, bFGF, BDNF and stromal cell-derivedfactor-1a in the sciatic nerve (40). However, theinteraction of these effects may exist at the sametime. Recently, mononuclear cells including PB-MNCs and BM-MNCs yield potential beneficialeffects for the treatment pDPN in preclinicalmodels. Naruse and Kim (41, 45) both con-firmed that BM- MNCs- induced amelioration inexperimental pDPN was associated with in-creased angiogenesis and neurotrophic factors inperipheral nerves. Moreover, MSCs may also bea good candidate for the treatment of pDPN.Shibata et al. (46) found that VEGF and bFGFmRNA expressions were significantly increasedin MSCs- injected thigh muscles of STZ- induceddiabetic rats. Interestingly, Kim et al. (47) report-ed that the levels of NGF and NT- 3, but notVEGF or bFGF were increased in diabetic ani-mals received BM-MNCs transplantation. Nota-bly, additional researches are required to under-stand the discrepancy in MSCs- induced neuro-trophic actions. However, it is clear that MSCswould be an optimal strategy in the treatment ofpDPN. Additionally, intraperitoneal administra-tion of MSC2, a protective MSCs phenotype,was shown to prevent thermal hyperalgesia, alle-viate mechanical allodynia, and facilitate the re-duction of pro-inflammatory cytokines in the se-rum level of pDPN mice (48), indicating thatother mechanisms (e.g., immunosuppression)might also exist. Alternatively, newly improvedinduced pluripotent stem cells (iPSCs) haveemerged as attractive tools for the treatment ofpDPN. Okawa et al. (49) suggested that iPSCs-derived neural crest- like cells can differentiateinto Schwann cell- like cells and vascular smoothmuscle cells, improve the impaired nerve andvascular functions, and produce growth factors(e.g., NGF, VEGF, NT- 3 and bFGF) in micewith pDPN. Based on the preclinical data, Com-erota et al. (50) treated a diabetes mellitus typeⅠ patient with 15 intramuscular injections of49- fold increased CD90 + mesenchymal cells ina case report. Dramatic pain relief of this pa-tient was reported two months later, and analge-sics were no longer needed and blood perfusionwas increased on laser Doppler imaging 6months later. After 9 months the patient had nopain and all the gangrenous and infected tissueswere healed.

Spinal Cord Injury Induced Chronic Pain

Spinal cord injury (SCI) is a serious central ner-vous system disease because it is associated withcatastrophic consequences in patients. Most SCIvictims suffer from chronic pain which is diffi-cult to manage or treat (51). Although somestudies suggest that various neuroanatomicaland neurochemical changes take place in thecentral nervous system after SCI, little is knownabout how these changes facilitate pain signal-ing. However, it has been generally acceptedthat hypofunction of the inhibitory pathways (e.g., GABAergic inhibitory system) contributes tomany pathological conditions including SCI- in-duced chronic pain (52). Furthermore, the re-duction of neurotrophic factors and the produc-tion of pro- inflammatory cytokines (e.g. IL- 1and TNF- α) in the injured spinal cord (53, 54)are other mechanisms that contribute to thepainful state. These pathological changes inhibitabnormal axon regeneration and nerve remyelin-ation (55) and thereby lead to aberrant regenera-tion and axonal sprouting.

Multiple types of cells, including stem cells,can be genetically modified and then transplant-ed as biological agents to release neurotransmit-ters and neurotrophins for therapeutic purposes(56, 57). Moreover, both in vitro and in vivostudies have shown that the special characteris-tics of stem cells are associated with their differ-entiation ability. For example, in vitro studies,NSCs may differentiate into neurons, astrocytesand oligodendrocytes, whereas when transplant-ed into spinal cord, NSCs give rise to glia (al-most exclusively astrocytes and only relativelyfew oligodendrocytes) and occasional neurons(6). Importantly, the glia cells play importantroles in synthesis, release, and uptake neu-rotransmitters (58). Stem cell derived astrocytesinduce anti-nociception by increasing the releaseof trophic factors (6, 59), which then counteractfactors that inhibit axonal regeneration. Stemcell derived oligodendrocytes play a critical rolein remyelination of spared axons within the in-jured white matter tracts (60). Together, stemcell transplantation may be a potential treatmentfor SCI- induced chronic pain through acting asa biologic minipump and differentiation.

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Despite the limitations and negative effects,NSCs transplantation is a potential treatment forSCI- related chronic pain. It has been generallyaccepted that genes of regulatory cytokines (e.g.,neurotransmitters and neurotrophic factors) thathave the desired therapeutic efficacy may be har-nessed to provide long- term pain relief. In ratswith SCI, a single subarachnoid injection ofhNT2.17 cells potently reversed tactile allodyniaand thermal hyperalgesia by acting as a“biologicminipump”to synthesize and release inhibitoryneurotransmitters γ- aminobutyric acid (GABA)and glycine in the lumbar subarachnoid space(61). In contrast, Melissa et al. (62) suggestedthat murine embryonic C17.2 NSCs lead to ther-mal and mechanical forelimb allodynia whentransplanted into the injured spinal cord in rats,whereas GDNF-transfected C17.2 NSCs (C17.2/GDNF) exert an analgesic effect on SCI- relatedpain by inhibiting neuronal sprouting. More-over, another preclinical study suggested thattransduction of NSCs with neurogenin- 2 beforetransplantation can suppress astrocytic differenti-ation, increase oligodendrocytes conversion, pre-vent graft- related sprouting and thereby reduceSCI- induced allodynia (6, 63). Yet, a major chal-lenge of developing NSCs- dependent strategiesfor the treatment of SCI- induced chronic pain istheir low transplant efficiency which restricts thetherapeutic potential (64). Accordingly, recent ef-forts have focused on identifying combinatorialstrategies to improve grafted cell survival in thehost damaged spinal cord. Olfactory ensheath-ing glial cells (OECs) were reported to promoteaxonal regeneration, reorganize the glial scar, re-myelinate axons and stimulate neural repair af-ter transplantation. Luo et al. (64) found that ad-ministion of NSCs and OECs together producean increase in analgesia by enhancing NSCs sur-vival and down regulating NGF expression. Simi-larly, neurotrophic factors were also found to actsynergistically with neural progenitor cells(NPCs) to optimize their integration into thehost spinal cord and facilitate oligodendrocytesdifferentiation (65). Taken together, these find-ings suggest that NSCs transplantation has a cru-cial role in pain remission in response to SCI.

Alternatively, a growing number of preclinicalexperiments and clinic trials suggest that MSCsmay also exhibit therapeutic effects on SCI (66).

In early preclinical studies, Yang et al. (67) re-ported that intraspinal transplantation of HU-MSCs derived from Wharton's jelly of the umbil-ical cord improves locomotor recovery, possiblyby increasing axon regeneration in the cortico-spinal tract and neurofilament- positive fibersaround the lesion. Although whether the trans-plantation relieves pain- related behavior is notknown, NT- 3 and bFGF produced by hUMSCsindicate a potential therapeutic evaluation forpain relief. Recently, Roh et al. (68) suggestedthat intraspinal transplantation of hAESCs orhUMSCs reduces mechanical allodynia in T13spinal cord hemisected rats both by reducing spi-nal cord microglia activity and NR1 phosphory-lation. Together, these data formed the basis forclinical trials to use MSCs in patients with SCI.In a case report, a patient with an incompleteT12- L1 spinal cord injury and a L1 vertebralbody crush fracture was treated with local trans-plantation of several cycles of MSCs andCD34 + cells. Allogeneic transplantation mark-edly decreased SCI-induced pain (from daily 10/10 to once a week 3/10 visual analogue scale)and significantly improved muscle strength ofthe patient (69). Overall, both preclinical studiesand clinical reports support the therapeutic ef-fect of MSCs in SCI-related chronic pain relief.

These preclinical and clinic data suggest stemcell transplantation would be an alternative strat-egy in attenuating SCI- induced chronic pain.However, additional researches are required tooptimize the function of stem cells and increasetheir clinical safety before further clinical appli-cation.

Summary

Stem cell transplantation can effectively relieveneuropathic pain under different pathologicalconditions. However, it is interesting to pointout that peripheral neuropathic pain seems to bemore responsive to stem cell therapy than SCI-induced chronic pain. Moreover, stem cell treat-ment does not always exert positive results inSCI- induced chronic pain (e.g. aggravating painabove the lesion spinal cord segment). Under-standing the molecular mechanisms underlyingboth positive and negative effects of stem cellson pain processing is very important for the de-

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Review Article

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velopment of novel, specific and effective thera-peutic modalities for pain relief. Stem cell re-searches should focus on both experimental andclinical studies of neuropathic pain in the future.In clinical trials, the type and dosage of the in-fused stem cells, the safety and the grafting effi-ciency should be further investigated. In animalresearches, the analgesic mechanisms of stem

cells in different animal models of neuropathicpain should be explored.

This work was supported by National Natural Science Foundation of China (

81428008, 81400909, 81571065), Beijing Natural Science Foundation

(7152056), the Excellent Program for Scientific Activity of Returned Oversea

Scholar, Beijing, China (2013), and the Program for High Levels of Health Per-

sonnel in Beijing City, China (2013).

No other potential conflict of interest relevant to this article was reported.

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Stem Cells and Neuropathic PainFang Xie et al.

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stem cell for the treatment of neuropathic pain...stem cell trans-plantation may be an important...

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