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Neurotrophic factors (NFs) play important roles in regenerative medicine approaches to mitigate primary and secondary damage after spinal cord injury (SCI) because their receptors are still present in the injured spinal cord even though the expression of the NFs themselves is decreased. Several reports have shown that NF administration increases regenerative signaling after SCI, particularly by stimulating axonal growth. However, few NFs cross the blood–brain barrier, and most of them show low stability and limited diffusion within the central nervous system. To overcome this problem, transplantation strategies using genetically modified NF-secreting Schwann cells, neural and glial progenitor cells, and mesenchymal stem cells have been applied to animal models of SCI. In particular, multifunctional NFs that bind to TrkB, TrkC, and p75NTR receptors have been discovered in the last decade and utilized in preclinical cell therapies for spinal cord repair. To achieve functional recovery after SCI, it is important to consider the different effects of each NF on axonal regeneration, and strategies should be established to specifically harness the multifunctional properties of NFs. This review provides an overview of multifunctional NFs combined with cell therapy in experimental SCI models and a proposal to implement their use as a clinically viable therapy.


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Therapeutic effects of neurotrophic factors in experimental spinal cord injury models

Show Author's information Mitsuhiro Enomoto1,2( )
Department of Orthopaedic and Spinal Surgery, Graduate School,
Hyperbaric Medical Center, Tokyo Medical and Dental University, Tokyo, Japan

Abstract

Neurotrophic factors (NFs) play important roles in regenerative medicine approaches to mitigate primary and secondary damage after spinal cord injury (SCI) because their receptors are still present in the injured spinal cord even though the expression of the NFs themselves is decreased. Several reports have shown that NF administration increases regenerative signaling after SCI, particularly by stimulating axonal growth. However, few NFs cross the blood–brain barrier, and most of them show low stability and limited diffusion within the central nervous system. To overcome this problem, transplantation strategies using genetically modified NF-secreting Schwann cells, neural and glial progenitor cells, and mesenchymal stem cells have been applied to animal models of SCI. In particular, multifunctional NFs that bind to TrkB, TrkC, and p75NTR receptors have been discovered in the last decade and utilized in preclinical cell therapies for spinal cord repair. To achieve functional recovery after SCI, it is important to consider the different effects of each NF on axonal regeneration, and strategies should be established to specifically harness the multifunctional properties of NFs. This review provides an overview of multifunctional NFs combined with cell therapy in experimental SCI models and a proposal to implement their use as a clinically viable therapy.

Keywords:

spinal cord injury, neurotrophic factor, multineurotrophin, regeneration, cell transplantation
Published: 23 March 2016 Issue date: December 2016
References(48)
1.
Jones LL, Oudega M, Bunge MB, Tuszynski MH. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol. 2001;533(Pt 1):83-89.
2.
Grill RJ, Blesch A, Tuszynski MH. Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp Neurol. 1997;148(2):444-452.
3.
Kobayashi NR, Fan DP, Giehl KM, Bedard AM, Wiegand SJ, Tetzlaff W. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration. J Neurosci. 1997;17(24):9583-9595.
4.
Bradbury EJ, Khemani S, Von R, King, Priestley JV, McMahon SB. NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord. Eur J Neurosci. 1999;11(11):3873-3883.
5.
Hiebert GW, Khodarahmi K, McGraw J, Steeves JD, Tetzlaff W. Brain-derived neurotrophic factor applied to the motor cortex promotes sprouting of corticospinal fibers but not regeneration into a peripheral nerve transplant. J Neurosci Res. 2002;69(2):160-168.
6.
Sayer FT, Oudega M, Hagg T. Neurotrophins reduce degeneration of injured ascending sensory and corticospinal motor axons in adult rat spinal cord. Exp Neurol. 2002;175(1):282-296.
7.
Urfer R, Tsoulfas P, Soppet D, Escandón E, Parada LF, Presta LG. The binding epitopes of neurotrophin-3 to its receptors trkC and gp75 and the design of a multifunctional human neurotrophin. EMBO J. 1994;13(24):5896-5909.
8.
Ruozi B, Belletti D, Bondioli L, et al. Neurotrophic factors and neurodegenerative diseases: a delivery issue. Int Rev Neurobiol. 2012;102:207-247.
9.
Mothe AJ, Tator CH. Advances in stem cell therapy for spinal cord injury. J Clin Invest. 2012;122(11):3824-3834.
10.
Ruff CA, Wilcox JT, Fehlings MG. Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol. 2012;235(1):78-90.
11.
Azari MF, Mathias L, Ozturk E, Cram DS, Boyd RL, Petratos S. Mesenchymal stem cells for treatment of CNS injury. Curr Neuropharmacol. 2010;8(4):316-323.
12.
Fehlings MG, Vawda R. Cellular treatments for spinal cord injury: the time is right for clinical trials. Neurotherapeutics. 2011;8(4):704-720.
13.
Murray M, Kim D, Liu Y, Tobias C, Tessler A, Fischer I. Transplantation of genetically modified cells contributes to repair and recovery from spinal injury. Brain Res Brain Res Rev. 2002;40(1-3):292-300.
14.
Watabe K, Fukuda T, Tanaka J, Honda H, Toyohara K, Sakai O. Spontaneously immortalized adult mouse Schwann cells secrete autocrine and paracrine growth-promoting activities. J Neurosci Res. 1995;41(2):279-290.
15.
Enomoto M, Bunge MB, Tsoulfas P. A multifunctional neurotrophin with reduced affinity to p75NTR enhances transplanted Schwann cell survival and axon growth after spinal cord injury. Exp Neurol. 2013;248:170-182.
16.
Flora G, Joseph G, Patel S, et al. Combining neurotrophin-transduced schwann cells and rolipram to promote functional recovery from subacute spinal cord injury. Cell Transplant. 2013;22(12):2203-2217.
17.
Golden KL, Pearse DD, Blits B, et al. Transduced Schwann cells promote axon growth and myelination after spinal cord injury. Exp Neurol. 2007;207(2):203-217.
18.
Hurtado A, Moon LD, Maquet V, Blits B, Jérôme R, Oudega M. Poly (D,L-lactic acid) macroporous guidance scaffolds seeded with Schwann cells genetically modified to secrete a bi-functional neurotrophin implanted in the completely transected adult rat thoracic spinal cord. Biomaterials. 2006;27(3):430-442.
19.
Kanno H, Pressman Y, Moody A, et al. Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci. 2014;34(5):1838-1855.
20.
Widenfalk J, Lundströmer K, Jubran M, Brene S, Olson L. Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci. 2001;21(10):3457-3475.
21.
Liebl DJ, Huang W, Young W, Parada LF. Regulation of Trk receptors following contusion of the rat spinal cord. Exp Neurol. 2001;167(1):15-26.
22.
Castellanos DA, Tsoulfas P, Frydel BR, Gajavelli S, Bes JC, Sagen J. TrkC overexpression enhances survival and migration of neural stem cell transplants in the rat spinal cord. Cell Transplant. 2002;11(3):297-307.
23.
Teng KK, Felice S, Kim T, Hempstead BL. Understanding proneurotrophin actions: recent advances and challenges. Dev Neurobiol. 2010;70(5):350-359.
24.
Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther. 2013;138(2):155-175.
25.
Awad BI, Carmody MA, Steinmetz MP. Potential role of growth factors in the management of spinal cord injury. World Neurosurg. 2015;83(1):120-131.
26.
Ledda F, Paratcha G, Sandoval-Guzmán T, Ibáñez CF. GDNF and GFRalpha1 promote formation of neuronal synapses by ligand-induced cell adhesion. Nat Neurosci. 2007;10(3):293-300.
27.
Deng LX, Deng P, Ruan Y, et al. A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci. 2013;33(13):5655-5667.
28.
Dougherty KD, Dreyfus CF, Black IB. Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis. 2000;7(6 Pt B):574-585.
29.
Hawryluk GW, Mothe A, Wang J, Wang S, Tator C, Fehlings MG. An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells Dev. 2012;21(12):2222-2238.
30.
Hendriks WT, Ruitenberg MJ, Blits B, Boer GJ, Verhaagen J. Viral vector-mediated gene transfer of neurotrophins to promote regeneration of the injured spinal cord. Prog Brain Res. 2004;146:451-476.
31.
Dittrich F, Ochs G, Grosse-Wilde A, et al. Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons. Exp Neurol. 1996;141(2):225-239.
32.
Abdellatif AA, Pelt JL, Benton RL, et al. Gene delivery to the spinal cord: comparison between lentiviral, adenoviral, and retroviral vector delivery systems. J Neurosci Res. 2006;84(3):553-567.
33.
Morrissey TK, Kleitman N, Bunge RP. Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci. 1991;11(8):2433-2442.
34.
Levi AD, Bunge RP, Lofgren JA, et al. The influence of heregulins on human Schwann cell proliferation. J Neurosci. 1995;15(2):1329-1340.
35.
Xu XM, Guénard V, Kleitman N, Aebischer P, Bunge MB. A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol. 1995;134(2):261-272.
36.
Blits B, Kitay BM, Farahvar A, Caperton CV, Dietrich WD, Bunge MB. Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue. Restor Neurol Neurosci. 2005;23(5-6):313-324.
37.
Cao Q, Xu XM, Devries WH, et al. Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci. 2005;25(30):6947-6957.
38.
Kusano K, Enomoto M, Hirai T, et al. Transplanted neural progenitor cells expressing mutant NT3 promote myelination and partial hind limb recovery in the chronic phase after spinal cord injury. Biochem Biophys Res Commun. 2010;393(4):812-817.
39.
Fan C, Zheng Y, Cheng X, et al. Transplantation of D15A-expressing glial-restricted-precursor-derived astrocytes improves anatomical and locomotor recovery after spinal cord injury. Int J Biol Sci. 2013;9(1):78-93.
40.
Dubreuil CI, Winton MJ, McKerracher L. Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J Cell Biol. 2003;162(2):233-243.
41.
Gong Y, Cao P, Yu HJ, Jiang T. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature. 2008;454(7205):789-793.
42.
He XL, Garcia KC. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science. 2004;304(5672):870-875.
43.
Mirsky R, Jessen KR. The neurobiology of Schwann cells. Brain Pathol. 1999;9(2):293-311.
44.
Syroid DE, Maycox PJ, Soilu-Hänninen M, et al. Induction of postnatal schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy. J Neurosci. 2000;20(15):5741-5747.
45.
Bradbury EJ, Moon LD, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002;416(6881):636-640.
46.
Kumagai G, Tsoulfas P, Toh S, McNiece I, Bramlett HM, Dietrich WD. Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury. Exp Neurol. 2013;248:369-380.
47.
Caporali A, Pani E, Horrevoets AJ, et al. Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. Circ Res. 2008;103(2):e15-e26.
48.
Ngen EJ, Wang L, Kato Y, et al. Imaging transplanted stem cells in real time using an MRI dual-contrast method. Sci Rep. 2015;5:13628.
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Published: 23 March 2016
Issue date: December 2016

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© 2016 The Author(s).

Acknowledgements

This work was supported in part by the Ministry of Health, Labour, and Welfare Sciences Research Grant, a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science, and a Grant-in-Aid from the General Insurance Association of Japan. The author is grateful to Prof K Shinomiya (Yokohama City Minato Red Cross Hospital), Prof A Okawa (Tokyo Medical and Dental University), and Dr P Tsoulfas (The Miami Project to Cure Paralysis) for their advice and generous support. The author thanks Dr K Fukushima, Dr F Numano, Dr K Kusano, Dr T Hirai, Dr M Onuma-Ukegawa, and Dr H Kaburagi for their continuous support for his research in SCI.

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© 2016 Enomoto. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).

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