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Year : 2014  |  Volume : 9  |  Issue : 5  |  Page : 458-459

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain

1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Basic Medical College, Zhengzhou University, Zhengzhou, Henan Province, China
2 Basic Medical College, Zhengzhou University, Zhengzhou; Basic Medical College, Xinxiang Medical University, Xinxiang, Henan Province, China
3 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Date of Acceptance02-Mar-2014
Date of Web Publication9-May-2014

Correspondence Address:
Ph.D. Feng Tao
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 355, Baltimore, MD 21205
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1673-5374.130057

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How to cite this article:
Liu S, Li C, Xing Y, Tao F. Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain. Neural Regen Res 2014;9:458-9

How to cite this URL:
Liu S, Li C, Xing Y, Tao F. Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain. Neural Regen Res [serial online] 2014 [cited 2019 Sep 15];9:458-9. Available from: http://www.nrronline.org/text.asp?2014/9/5/458/130057

Spinal cord injury (SCI) currently ranks second after mental retardation among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues (Yezierski, 2005; D'Angelo et al., 2013). Approximately two-thirds of persons who have sustained SCI experience clinically significant pain after injury, of whom one-third have severe pain (Finnerup et al., 2001; Siddall et al., 2003). Post-SCI pain can increase with time and is often refractory to conventional treatment approaches (Rintala et al., 1998). Over the past decade, clinical studies have shown that post-SCI pain interferes with rehabilitation, daily activities, and quality of life and may substantially influence mood, leading to depression and even suicide (Segatore, 1994; Rintala et al., 1998; Westgren and Levi, 1998; Widerstrom-Noga et al., 2001).Chronic neuropathic pain following SCI is divided into three types: at-level pain (pain within the body segments innervated by spinal cord segments at the level of the injury), below-level pain (pain within body segments caudal to the level at which the spinal cord was injured), and above-level pain (pain within body segments rostral to the level at which the spinal cord was injured) (Waxman and Hains, 2006). The mechanisms underlying SCI-induced chronic neuropathic pain are not well understood. Aberrant central sprouting of nociceptive fibers has been commonly proposed as a mechanism of SCI pain and is associated with mechanical allodynia induced by SCI (Christensen and Hulsebosch, 1997; Yezierski, 2000; Finnerup and Jensen, 2004). Demyelination (loss of myelin) and dysmyelination (abnormal myelination) induced by oligodendrocyte injury and death are important contributors to SCI-associated behavioral deficits, including pain (Bunge et al., 1961; Blight, 1983; Bunge et al., 1993; Liu et al., 1997; Becker et al., 2003). For instance, SCI-induced dysmyelination is involved in the aberrant sprouting of nociceptive fibers and causes SCI pain behaviors. Thus, remyelination of demyelinated/dysmyelinated axons in the injured spinal cord could be an important repair therapy for SCI and one of the key elements for functional recovery and aberrant sprouting prevention after SCI (McDonald and Belegu, 2006; Plemel et al., 2014).

SCI pain is extremely debilitating and remains largely unmanageable by current therapeutic strategies. In the past decade, experimental studies on stem cell therapy for SCI-induced chronic neuropathic pain have emerged and sparked tremendous interest in this once obscure field. In preclinical research, predifferentiated ES cells prevented chronic pain behaviors and restored sensory function following SCI in mice (Hendricks et al., 2006), and subarachnoid transplant of a human γ-aminobutyric acid-secreting neuronal cell line, hNT2.17, attenuated chronic allodynia and hyperalgesia after excitotoxic SCI in rats (Eaton et al., 2007). However, grafting of neural stem cells (NSCs) caused aberrant axonal sprouting associated with allodynia-like forelimb hypersensitivity in a rat contusion SCI model (Hofstetter et al., 2005; Macias et al., 2006). In contrast, transduction of NSCs with neurogenin-2 before transplantation differentiated cells into oligodendrocytes and prevented graft-induced sprouting and allodynia. Moreover, the transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area and recovery of hind limb locomotor function and sensory responses (Hofstetter et al., 2005; Klein and Svendsen, 2005). These results suggest that increasing the production of oligodendrocytes reduces allodynia and improves functional recovery.

Given that a substantial cause of neurological deficits after SCI is oligodendrocyte death leading to demyelination and dysmyelination, the goal of stem cell transplantation should be guided to promote remyelination of spared axons in the injured spinal cord. It is now recognized that oligodendrocytes are important near-term clinical targets for restoring function after CNS injury, particularly SCI. Thus, directed differentiation of stem cells to oligodendrocyte precursors prior to transplantation may be an effective strategy to increase the extent of remyelination for the treatment of SCI. For remyelination, oligodendrocyte precursors must further differentiate into mature oligodendrocytes. However, the transplanted OPCs cannot survive for a long time and many of them cannot mature into myelinating oligodendrocytes. Previous studies have demonstrated that appropriate trophic modulation of the microenvironment in the injured spinal cord can promote oligodendroglial differentiation and maturation (Barres and Raff, 1994; Barres et al., 1994; Kumar et al., 1998; McTigue et al., 1998; Yan and Wood, 2000; Franklin et al., 2001; Cosgaya et al., 2002; Jean et al., 2003; Karimi-Abdolrezaee et al., 2012).

Neurotrophins [such as neurotrophin 3 (NT3) and brain-derived neurotrophic factor (BDNF)] play key roles in OPC proliferation and myelin formation. D15A is a multineurotrophin that binds to neurotrophin receptors trkB and trkC and has both BDNF and NT3 activities (Urfer et al., 1994; Strohmaier et al., 1996). NT3 and BDNF regulate neuronal development and axonal regeneration (Xu et al., 1995; Zhou and Shine, 2003). They are also important mediators of myelination. Mice that lack functional trkC or NT3 are deficient in both mature oligodendrocytes and OPCs (Kumar et al., 1998). NT3 enhances the survival and proliferation of OPCs in vitro (Barres and Raff, 1994; Kumar et al., 1998; Yan and Wood, 2000; Franklin et al., 2001) and in vivo (Barres et al., 1994). Myelination produced byoligodendrocytes is also enhanced by NT3 in cultured neurons and the injured CNS (McTigue et al., 1998; Yan and Wood, 2000; Jean et al., 2003). BDNF is known to be important for myelin formation during development because inactivation of BDNF signaling by deletion of trkB receptors causes myelin deficits both in vivo and in vitro (Cosgaya et al., 2002). Treatment with neurotrophins and glial-restricted precursor cell grafts promotes differentiation of oligodendrocyte lineage and facilitates functional recovery after traumatic SCI (Cao et al., 2005). Taken together, these results suggest that appropriate trophic modulation of the molecular microenvironment in the injured spinal cord can affect differentiation and maturation of transplanted stem cells and that the combination strategy with stem cell graft and microenvironment modulation can be used to enhance therapeutic efficacy of cell transplantation.

SCI is a serious clinical condition that results in persistent motor and sensory deficits. Patients with SCI, who often are injured at an early age, experience life-long alterations in quality of life. Functional deficits following SCI result from damage to axons, loss of neurons and glia, and demyelination/dysmyelination in the injured spinal cord (Totoiu and Keirstead, 2005). Thus, remyelination appears to be one of the most feasible restoration strategies for SCI treatment. Animal studies from our laboratory and others have shown that stem cell transplantation with OPCs could produce remyelination in the injured spinal cord and partially improve functional recovery after SCI (Liu et al., 2000; Keirstead et al., 2005; Nistor et al., 2005; Tao et al., 2013). However, the efficacy of the cell transplantation approach is not significantly sufficient due to the transplanted OPCs' short-term survival and their low maturation rate in the injured spinal cord. Therefore, future studies should be conducted to explore a novel approach by combining stem cell grafting with microenvironment modulation to enhance stem cell therapy for SCI and SCI-induced pain.[43]

  References Top

1.Barres BA, Raff MC (1994) Control of oligodendrocyte number in the developing rat optic nerve. Neuron 12:935-942.  Back to cited text no. 1
2.Barres BA, Raff MC, Gaese F, Bartke I, Dechant G, Barde YA (1994) A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371-375.  Back to cited text no. 2
3.Becker D, Sadowsky CL, McDonald JW (2003) Restoring function after spinal cord injury. Neurologist 9:1-15.  Back to cited text no. 3
4.Blight AR (1983) Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling. Neuroscience 10:521-543.  Back to cited text no. 4
5.Bunge MB, Bunge RP, Ris H (1961) Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord. J Biophys Biochem Cytol 10:67-94.  Back to cited text no. 5
6.Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM (1993) Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 59:75-89.  Back to cited text no. 6
7.Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P, Wood PM, Bunge MB, Whittemore SR (2005) Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25:6947-6957.  Back to cited text no. 7
8.Christensen MD, Hulsebosch CE (1997) Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat. Exp Neurol 147:463-475.  Back to cited text no. 8
9.Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298:1245-1248.  Back to cited text no. 9
10.D'Angelo R, Morreale A, Donadio V, Boriani S, Maraldi N, Plazzi G, Liguori R (2013) Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management. Eur Rev Med Pharmacol Sci 17:3257-3261.  Back to cited text no. 10
11.Eaton MJ, Wolfe SQ, Martinez M, Hernandez M, Furst C, Huang J, Frydel BR, Gomez-Marin O (2007) Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain 8:33-50.  Back to cited text no. 11
12.Finnerup NB, Jensen TS (2004) Spinal cord injury pain--mechanisms and treatment. Eur J Neurol 11:73-82.  Back to cited text no. 12
13.Finnerup NB, Johannesen IL, Sindrup SH, Bach FW, Jensen TS (2001) Pain and dysesthesia in patients with spinal cord injury: A postal survey. Spinal cord 39:256-262.  Back to cited text no. 13
14.Franklin RJ, Hinks GL, Woodruff RH, O'Leary MT (2001) What roles do growth factors play in CNS remyelination? Prog Brain Res 132:185-193.  Back to cited text no. 14
15.Hendricks WA, Pak ES, Owensby JP, Menta KJ, Glazova M, Moretto J, Hollis S, Brewer KL, Murashov AK (2006) Predifferentiated embryonic stem cells prevent chronic pain behaviors and restore sensory function following spinal cord injury in mice. Mol Med 12:34-46.  Back to cited text no. 15
16.Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L (2005) Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 8:346-353.  Back to cited text no. 16
17.Jean I, Lavialle C, Barthelaix-Pouplard A, Fressinaud C (2003) Neurotrophin-3 specifically increases mature oligodendrocyte population and enhances remyelination after chemical demyelination of adult rat CNS. Brain Res 972:110-118.  Back to cited text no. 17
18.Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG (2012) Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One 7:e37589.  Back to cited text no. 18
19.Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O (2005) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:4694-4705.  Back to cited text no. 19
20.Klein S, Svendsen CN (2005) Stem cells in the injured spinal cord: reducing the pain and increasing the gain. Nat Neurosci 8:259-260.  Back to cited text no. 20
21.Kumar S, Kahn MA, Dinh L, de Vellis J (1998) NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo. J Neurosci Res 54:754-765.  Back to cited text no. 21
22.Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW (2000) Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A 97:6126-6131.  Back to cited text no. 22
23.Liu XZ, Xu XM, Hu R, Du C, Zhang SX, McDonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395-5406.  Back to cited text no. 23
24.Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN (2006) Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol 201:335-348.  Back to cited text no. 24
25.McDonald JW, Belegu V (2006) Demyelination and remyelination after spinal cord injury. J Neurotrauma 23:345-359.  Back to cited text no. 25
26.McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18:5354-5365.  Back to cited text no. 26
27.Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS (2005) Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49:385-396.  Back to cited text no. 27
28.Plemel JR, Keough MB, Duncan GJ, Sparling JS, Yong VW, Stys PK, Tetzlaff W (2014) Remyelination after spinal cord injury: Is it a target for repair? Prog Neurobiol Feb 28 [Epub ahead of print].  Back to cited text no. 28
29.Rintala DH, Loubser PG, Castro J, Hart KA, Fuhrer MJ (1998) Chronic pain in a community-based sample of men with spinal cord injury: prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being. Arch Phys Med Rehabil 79:604-614.  Back to cited text no. 29
30.Segatore M (1994) Understanding chronic pain after spinal cord injury. J Neurosci Nurs 26:230-236.  Back to cited text no. 30
31.Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ (2003) A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103:249-257.  Back to cited text no. 31
32.Strohmaier C, Carter BD, Urfer R, Barde YA, Dechant G (1996) A splice variant of the neurotrophin receptor trkB with increased specificity for brain-derived neurotrophic factor. EMBO J 15:3332-3337.  Back to cited text no. 32
33.Tao F, Li Q, Liu S, Wu H, Skinner J, Hurtado A, Belegu V, Furmanski O, Yang Y, McDonald JW, Johns RA (2013) Role of neuregulin-1/ErbB signaling in stem cell therapy for spinal cord injury-induced chronic neuropathic pain. Stem Cells 31:83-91.  Back to cited text no. 33
34.Totoiu MO, Keirstead HS (2005) Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486:373-383.  Back to cited text no. 34
35.Urfer R, Tsoulfas P, Soppet D, Escandon E, Parada LF, Presta LG (1994) The binding epitopes of neurotrophin-3 to its receptors trkC and gp75 and the design of a multifunctional human neurotrophin. EMBO J 13:5896-5909.  Back to cited text no. 35
36.Waxman SG, Hains BC (2006) Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci 29:207-215.  Back to cited text no. 36
37.Westgren N, Levi R (1998) Quality of life and traumatic spinal cord injury. Arch Phys Med Rehabil 79:1433-1439.  Back to cited text no. 37
38.Widerstrom-Noga EG, Felipe-Cuervo E, Yezierski RP (2001) Chronic pain after spinal injury: interference with sleep and daily activities. Arch Phys Med Rehabil 82:1571-1577.  Back to cited text no. 38
39.Xu XM, Guenard V, Kleitman N, Aebischer P, Bunge MB (1995) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261-272.  Back to cited text no. 39
40.Yan H, Wood PM (2000) NT-3 weakly stimulates proliferation of adult rat O1(-)O4(+) oligodendrocyte-lineage cells and increases oligodendrocyte myelination in vitro. J Neurosci Res 62:329-335.  Back to cited text no. 40
41.Yezierski RP (2000) Pain following spinal cord injury: pathophysiology and central mechanisms. Prog Brain Res 129:429-449.  Back to cited text no. 41
42.Yezierski RP (2005) Spinal cord injury: a model of central neuropathic pain. Neurosignals 14:182-193.  Back to cited text no. 42
43.Zhou L, Shine HD (2003) Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury. J Neurosci Res 74:221-226.  Back to cited text no. 43

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