nach oben

Acta Neurochirurgica

Erschienen in:

01.07.2014 | Experimental Research - Brain Injury

Transplantation of neurotrophin-3-expressing bone mesenchymal stem cells improves recovery in a rat model of spinal cord injury

verfasst von: Ling-Jie Wang, Rui-Ping Zhang, Jian-Ding Li

Erschienen in: Acta Neurochirurgica | Ausgabe 7/2014

Einloggen, um Zugang zu erhalten

Abstract

Background

This study aimed to investigate the therapeutic effects of transplanting neutrophin-3 (NT-3)-expressing bone marrow-derived mesenchymal stem cells (BMSCs) in a rat model of spinal cord injury (SCI).

Methods

Forty-eight adult female Sprague–Dawley rats were randomly assigned to three groups: the control, BMSC, and NT-3-BMSC groups. BMSCs were infected with NT-3-DsRed or DsRed lentivirus and injected into the cerebrospinal fluid (CSF) via lumbar puncture (LP) 7 days after SCI in the NT-3-BMSC and BMSC groups, respectively. The hind-limb motor function of all rats was recorded using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale on days 1, 3, 7, 14, 21, 28, and 35 after transplantation. Haematoxylin-eosin (HE) staining, immunofluorescence labelling, and western blotting were performed at the final time point.

Results

Expressions of NT-3, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) proteins increased significantly in the NT-3-BMSC group, and hind-limb locomotor functions improved significantly in the NT-3-BMSC group compared with the other two groups. The cystic cavity area was smallest in the NT-3-BMSC group. In the NT-3-BMSC group, neurofilament 200 (NF200) and glial fibrillary acidic protein (GFAP) expression levels around the lesions were significantly increased and decreased, respectively.

Conclusions

Our findings demonstrate that transplantation of NT-3 gene-modified BMSCs via LP can strengthen the therapeutic benefits of BMSC transplantation. We observed that these modified cells increased locomotor function recovery, promoted nerve regeneration, and improved the injured spinal cord microenvironment, suggesting that it could be a promising treatment for SCI.

Bakshi A, Hunter C, Swanger S, Lepore A, Fischer I (2004) Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J Neurosurg Spine 1:330–337PubMedCrossRef

Barouch R, Schwartz M (2002) Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J 16:1304–1306PubMed

Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21PubMedCrossRef

Besser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162:6303–6306PubMed

Chopp M, Li Y (2002) Treatment of neural injury with marrow stromal cells. Lancet Neurol 1:92–100PubMedCrossRef

Constantini S, Young W (1994) The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats. J Neurosurg 80:97–111PubMedCrossRef

Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG (2006) Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198:54–64PubMedCrossRef

Dougherty KD, Dreyfus CF, Black IB (2000) Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis 7:574–585PubMedCrossRef

Douglas-Escobar M, Rossignol C, Steindler D, Zheng T, Weiss MD (2012) Neurotrophin-induced migration and neuronal differentiation of multipotent astrocytic stem cells in vitro. PLoS ONE 7:e51706PubMedCentralPubMedCrossRef

10.

Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521PubMed

11.

Fujiwara Y, Tanaka N, Ishida O, Fujimoto Y, Murakami T, Kajihara H, Yasunaga Y, Ochi M (2004) Intravenously injected neural progenitor cells of transgenic rats can migrate to the injured spinal cord and differentiate into neurons, astrocytes and oligodendrocytes. Neurosci Lett 366:287–291PubMedCrossRef

12.

Goldberg JL, Barres BA (2000) The relationship between neuronal survival and regeneration. Annu Rev Neurosci 23:579–612PubMedCrossRef

13.

Guo JS, Zeng YS, Li HB, Huang WL, Liu RY, Li XB, Ding Y, Wu LZ, Cai DZ (2007) Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury. Spinal Cord 45:15–24PubMedCrossRef

14.

Hawryluk GW, Mothe A, Wang J, Wang S, Tator C, Fehlings MG (2012) 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 21:2222–2238PubMedCentralPubMedCrossRef

15.

Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 99:2199–2204PubMedCentralPubMedCrossRef

16.

Ji JF, He BP, Dheen ST, Tay SS (2004) Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 22:415–427PubMedCrossRef

17.

Johnson PJ, Parker SR, Sakiyama-Elbert SE (2009) Controlled release of neurotrophin-3 from fibrin-based tissue engineering scaffolds enhances neural fiber sprouting following subacute spinal cord injury. Biotechnol Bioeng 104:1207–1214PubMedCentralPubMedCrossRef

18.

Kamei N, Tanaka N, Oishi Y, Hamasaki T, Nakanishi K, Sakai N, Ochi M (2007) BDNF, NT-3, and NGF released from transplanted neural progenitor cells promote corticospinal axon growth in organotypic cocultures. Spine (Phila Pa 1976) 32:1272–1278CrossRef

19.

Kamei N, Tanaka N, Oishi Y, Ishikawa M, Hamasaki T, Nishida K, Nakanishi K, Sakai N, Ochi M (2007) Bone marrow stromal cells promoting corticospinal axon growth through the release of humoral factors in organotypic cocultures in neonatal rats. J Neurosurg Spine 6:412–419PubMedCrossRef

20.

Kan EM, Ling EA, Lu J (2010) Stem cell therapy for spinal cord injury. Curr Med Chem 17:4492–4510PubMedCrossRef

21.

Kang ES, Ha KY, Kim YH (2012) Fate of transplanted bone marrow derived mesenchymal stem cells following spinal cord injury in rats by transplantation routes. J Korean Med Sci 27:586–593PubMedCentralPubMedCrossRef

22.

Kubinova S, Sykova E (2012) Biomaterials combined with cell therapy for treatment of spinal cord injury. Regen Med 7:207–224PubMedCrossRef

23.

Laurenzi MA, Barbany G, Timmusk T, Lindgren JA, Persson H (1994) Expression of mRNA encoding neurotrophins and neurotrophin receptors in rat thymus, spleen tissue and immunocompetent cells. Regulation of neurotrophin-4 mRNA expression by mitogens and leukotriene B4. Eur J Biochem 223:733–741PubMedCrossRef

24.

Li Y, Zhang WM, Wang TH (2011) Optimal location and time for neural stem cell transplantation into transected rat spinal cord. Cell Mol Neurobiol 31:407–414PubMedCrossRef

25.

Lin WP, Chen XW, Zhang LQ, Wu CY, Huang ZD, Lin JH (2013) Effect of neuroglobin genetically modified bone marrow mesenchymal stem cells transplantation on spinal cord injury in rabbits. PLoS ONE 8:e63444PubMedCentralPubMedCrossRef

26.

Liu WG, Wang ZY, Huang ZS (2011) Bone marrow-derived mesenchymal stem cells expressing the bFGF transgene promote axon regeneration and functional recovery after spinal cord injury in rats. Neurol Res 33:686–693PubMedCrossRef

27.

Loane DJ, Byrnes KR (2010) Role of microglia in neurotrauma. Neurotherapeutics 7:366–377PubMedCentralPubMedCrossRef

28.

Massey JM, Amps J, Viapiano MS, Matthews RT, Wagoner MR, Whitaker CM, Alilain W, Yonkof AL, Khalyfa A, Cooper NG, Silver J, Onifer SM (2008) Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol 209:426–445PubMedCentralPubMedCrossRef

29.

Murray M (2004) Cellular transplants: steps toward restoration of function in spinal injured animals. Prog Brain Res 143:133–146PubMed

30.

Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G, Fischer I (2005) Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 1035:73–85PubMedCrossRef

31.

Nishida K, Tanaka N, Nakanishi K, Kamei N, Hamasaki T, Yanada S, Mochizuki Y, Ochi M (2006) Magnetic targeting of bone marrow stromal cells into spinal cord: through cerebrospinal fluid. Neuroreport 17:1269–1272PubMedCrossRef

32.

Ohta M, Suzuki Y, Noda T, Ejiri Y, Dezawa M, Kataoka K, Chou H, Ishikawa N, Matsumoto N, Iwashita Y, Mizuta E, Kuno S, Ide C (2004) Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol 187:266–278PubMedCrossRef

33.

Okano H, Ogawa Y, Nakamura M, Kaneko S, Iwanama A, Toyama Y (2003) Transplantation of neural stem cells into the spinal cord after injury. Semin Cell Dev Biol 14:191–198PubMedCrossRef

34.

Parr AM, Kulbatski I, Wang XH, Keating A, Tator CH (2008) Fate of transplanted adult neural stem/progenitor cells and bone marrow-derived mesenchymal stromal cells in the injured adult rat spinal cord and impact on functional recovery. Surg Neurol 70:600–607, discussion 607PubMedCrossRef

35.

Parr AM, Tator CH, Keating A (2007) Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 40:609–619PubMedCrossRef

36.

Patapoutian A, Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11:272–280PubMedCrossRef

37.

Pyle AD, Lock LF, Donovan PJ (2006) Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnol 24:344–350PubMedCrossRef

38.

Rabchevsky AG, Streit WJ (1998) Role of microglia in post injury repair and regeneration of the CNS. Ment Retard Dev Disabil Res Rev 4:187–192CrossRef

39.

Rosenstein JM, Krum JM (2004) New roles for VEGF in nervous tissue—beyond blood vessels. Exp Neurol 187:246–253PubMedCrossRef

40.

Sahni V, Kessler JA (2010) Stem cell therapies for spinal cord injury. Nat Rev Neurol 6:363–372PubMedCentralPubMedCrossRef

41.

Sasaki H, Tanaka N, Nakanishi K, Nishida K, Hamasaki T, Yamada K, Ochi M (2011) Therapeutic effects with magnetic targeting of bone marrow stromal cells in a rat spinal cord injury model. Spine (Phila Pa 1976) 36:933–938CrossRef

42.

Satake K, Lou J, Lenke LG (2004) Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue. Spine (Phila Pa 1976) 29:1971–1979CrossRef

43.

Schiller MD, Mobbs RJ (2012) The historical evolution of the management of spinal cord injury. J Clin Neurosci 19:1348–1353PubMedCrossRef

44.

Shang AJ, Hong SQ, Xu Q, Wang HY, Yang Y, Wang ZF, Xu BN, Jiang XD, Xu RX (2011) NT-3-secreting human umbilical cord mesenchymal stromal cell transplantation for the treatment of acute spinal cord injury in rats. Brain Res 1391:102–113PubMedCrossRef

45.

Shen J, Zhong XM, Duan XH, Cheng LN, Hong GB, Bi XB, Liu Y (2009) Magnetic resonance imaging of mesenchymal stem cells labeled with dual (MR and fluorescence) agents in rat spinal cord injury. Acad Radiol 16:1142–1154PubMedCrossRef

46.

Shen L, Zeng W, Wu YX, Hou CL, Chen W, Yang MC, Li L, Zhang YF, Zhu CH (2013) Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. Cell Transplant 22:1011–1021PubMedCrossRef

47.

Shumsky JS, Tobias CA, Tumolo M, Long WD, Giszter SF, Murray M (2003) Delayed transplantation of fibroblasts genetically modified to secrete BDNF and NT-3 into a spinal cord injury site is associated with limited recovery of function. Exp Neurol 184:114–130PubMedCrossRef

48.

Sieck GC, Mantilla CB (2009) Role of neurotrophins in recovery of phrenic motor function following spinal cord injury. Respir Physiol Neurobiol 169:218–225PubMedCentralPubMedCrossRef

49.

Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24:1254–1264PubMedCrossRef

50.

Song XY, Li F, Zhang FH, Zhong JH, Zhou XF (2008) Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS ONE 3:e1707PubMedCentralPubMedCrossRef

51.

Sykova E, Jendelova P (2005) Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord. Ann N Y Acad Sci 1049:146–160PubMedCrossRef

52.

Tetzlaff W, Okon EB, Karimi-Abdolrezaee S, Hill CE, Sparling JS, Plemel JR, Plunet WT, Tsai EC, Baptiste D, Smithson LJ, Kawaja MD, Fehlings MG, Kwon BK (2011) A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 28:1611–1682PubMedCentralPubMedCrossRef

53.

Thuret S, Moon LD, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7:628–643PubMedCrossRef

54.

Ullal GR, Michalski B, Xu B, Racine RJ, Fahnestock M (2007) NT-3 modulates BDNF and proBDNF levels in naive and kindled rat hippocampus. Neurochem Int 50:866–871PubMedCrossRef

55.

Vanecek V, Zablotskii V, Forostyak S, Růžička J, Herynek V, Babič M, Jendelová P, Kubinová S, Dejneka A, Syková E (2012) Highly efficient magnetic targeting of mesenchymal stem cells in spinal cord injury. Int J Nanomedicine 7:3719–3730PubMedCentralPubMedCrossRef

56.

White RE, Jakeman LB (2008) Don’t fence me in: harnessing the beneficial roles of astrocytes for spinal cord repair. Restor Neurol Neurosci 26:197–214PubMedCentralPubMed

57.

Widenfalk J, Lipson A, Jubran M, Hofstetter C, Ebendal T, Cao Y, Olson L (2003) Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury. Neuroscience 120:951–960PubMedCrossRef

58.

Wright KT, El Masri W, Osman A, Chowdhury J, Johnson WE (2011) Concise review: bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications. Stem Cells 29:169–178PubMedCentralPubMedCrossRef

59.

Wu S, Suzuki Y, Ejiri Y, Noda T, Bai H, Kitada M, Kataoka K, Ohta M, Chou H, Ide C (2003) Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res 72:343–351PubMedCrossRef

60.

Yaghoobi MM, Mowla SJ (2006) Differential gene expression pattern of neurotrophins and their receptors during neuronal differentiation of rat bone marrow stromal cells. Neurosci Lett 397:149–154PubMedCrossRef

61.

Zhang W, Yan Q, Zeng YS, Zhang XB, Xiong Y, Wang JM, Chen SJ, Li Y, Bruce IC, Wu W (2010) Implantation of adult bone marrow-derived mesenchymal stem cells transfected with the neurotrophin-3 gene and pretreated with retinoic acid in completely transected spinal cord. Brain Res 1359:256–271PubMedCrossRef

62.

Zhao T, Yan W, Xu K, Qi Y, Dai X, Shi Z (2013) Combined treatment with platelet-rich plasma and brain-derived neurotrophic factor-overexpressing bone marrow stromal cells supports axonal remyelination in a rat spinal cord hemi-section model. Cytotherapy 15:792–804PubMedCrossRef

Titel: Transplantation of neurotrophin-3-expressing bone mesenchymal stem cells improves recovery in a rat model of spinal cord injury
verfasst von: Ling-Jie Wang
Rui-Ping Zhang
Jian-Ding Li
Publikationsdatum: 01.07.2014
Verlag: Springer Vienna
Erschienen in: Acta Neurochirurgica / Ausgabe 7/2014
Print ISSN: 0001-6268
Elektronische ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-014-2089-6

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Viel Bewegung in der Parkinsonforschung

25.04.2024 Parkinson-Krankheit Nachrichten

Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2014

Microsurgical reconstruction of the cauda equina after traumatic transecting injury

Diagnostic dyspraxia by disrupted fiber connections of the posterior corpus callosum after distal anterior cerebral artery aneurysm rupture

Use of the bovine pericardial patch and fibrin sealant in meningomyelocele closure

Avoidance of postoperative epistaxis and anosmia in endonasal endoscopic skull base surgery: a technical note

Effect of amantadine in minimally conscious state of non-traumatic etiology