Skip to main content

Advertisement

SpringerLink
Log in

Neural Stem Cells Over-Expressing Brain-Derived Neurotrophic Factor (BDNF) Stimulate Synaptic Protein Expression and Promote Functional Recovery Following Transplantation in Rat Model of Traumatic Brain Injury

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Brain-derived neurotrophic factor (BDNF) plays an essential regulatory role in the survival and differentiation of various neural cell types during brain development and after injury. In this study, we used neural stem cells (NSCs) genetically modified to encode BDNF gene (BDNF/NSCs) and naive NSCs transplantation and found that BDNF/NSCs significantly improved neurological motor function following traumatic brain injury (TBI) on selected behavioral tests. Our data clearly demonstrate that the transplantation of BDNF/NSCs causes overexpression of BDNF in the brains of TBI rats. The number of surviving engrafted cells and the proportion of engrafted cells with a neuronal phenotype were significantly greater in BDNF/NSCs than in naive NSCs-transplanted rats. The expression of pre- and post-synaptic proteins and a regeneration-associated gene in the BDNF/NSCs-transplanted rats was significantly increased compared to that in NSCs-transplanted rats, especially at the early stage of post-transplantation. These data suggest that neurite growth and overexpression of synaptic proteins in BDNF/NSCs-transplanted rats are associated with the overexpression of BDNF, which is hypothesized to be one of the mechanisms underlying the improved functional recovery in motor behavior at the early stage of cell transplantation following TBI. Therefore, the protective effect of the BDNF-modified NSCs transplantation is greater than that of the naive NSCs transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Shames J, Treger I, Ring H et al (2007) Return to work following traumatic brain injury: trends and challenges. Disabil Rehabil 29:1387–1395

    Article  PubMed  Google Scholar 

  2. Aebischer P, Goddard M, Signore AP et al (1994) Functional recovery in hemiparkinsonian primates transplanted with polymerencapsulated PC12 cells. Exp Neurol 126:151–158

    Article  PubMed  CAS  Google Scholar 

  3. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438

    Article  PubMed  CAS  Google Scholar 

  4. Lindvall O, Kokaia Z, Martinez-Serrano A (2004) Stem cell therapy for human neurodegenerative disorders: how to make it work? Nat Med 10:42–50

    Article  Google Scholar 

  5. Benninger Y, Marino S, Hardegger R et al (2000) Differentiation and histological analysis of embryonic stem cell-derived neural transplants in mice. Brain Pathol 10:330–341

    Article  PubMed  CAS  Google Scholar 

  6. Harting MT, Sloan LE, Jimenez F et al (2009) Subacute neural stem cell therapy for traumatic brain injury. J Surg Res 153:188–194

    Article  PubMed  CAS  Google Scholar 

  7. Lenzlinger PM, Morganti-Kossmann MC, Laurer HL et al (2001) The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol 24:169–181

    Article  PubMed  CAS  Google Scholar 

  8. Modo M, Stroemer P, Tang E et al (2002) Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage. Stroke 33:2270–2278

    Article  PubMed  Google Scholar 

  9. Zhang L, Zhang HT, Hong SQ et al (2009) Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochem Res 34:2030–2039

    Article  PubMed  CAS  Google Scholar 

  10. Willson ML, McElnea C, Mariani J et al (2008) BDNF increases homotypic olivocerebellar reinnervation and associated fine motor and cognitive skill. Brain 131:1099–1112

    Article  PubMed  Google Scholar 

  11. Kaplan GB, Vasterling JJ, Vedak PC (2010) Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder, and their comorbid conditions: role in pathogenesis and treatment. Behav Pharmacol 21:427–437

    Article  PubMed  CAS  Google Scholar 

  12. Ahmed S, Reynolds BA, Weiss S (1995) BDNF enhances the differentiation but not the survival of CNS stem cell- derived neuronal precursors. J Neurosci 15:5765–5778

    PubMed  CAS  Google Scholar 

  13. Mahmood A, Lu D, Wang L et al (2002) Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. J Neurotrauma 19:1609–1617

    Article  PubMed  Google Scholar 

  14. Islam O, Loo TX, Heese K (2009) Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res 6:42–53

    Article  PubMed  CAS  Google Scholar 

  15. Moro K, Shiotani A, Watabe K et al (2006) Adenoviral gene transfer of BDNF and GDNF synergistically prevent motoneuron loss in the nucleus ambiguus. Brain Res 1076:1–8

    Article  PubMed  CAS  Google Scholar 

  16. Kwon BK, Liu J, Lam C et al (2007) Brain-derived neurotrophic factor gene transfer with adeno-associated viral and lentiviral vectors prevents rubrospinal neuronal atrophy and stimulates regeneration-associated gene expression after acute cervical spinal cord injury. Spine 32:1164–1173

    Article  PubMed  Google Scholar 

  17. Ma XH, Shi Y, Hou Y et al (2010) Slow-freezing cryopreservation of neural stem cell spheres with different diameters. Cryobiology 60:184–191

    Article  PubMed  CAS  Google Scholar 

  18. Iwamoto Y, Yang K, Clifton GL et al (1996) Liposome-mediated BDNF cDNA transfer in intact and injured rat brain. Neuroreport 7:609–612

    Article  PubMed  CAS  Google Scholar 

  19. Boockvar JA, Schouten J, Royo N et al (2005) Experimental traumatic brain injury modulates the survival, migration, and terminal phenotype of transplanted epidermal growth factor receptor-activated neural stem cells. Neurosurgery 56:163–171

    PubMed  Google Scholar 

  20. Fauza DO, Jennings RW, Teng YD et al (2008) Neural stem cell delivery to the spinal cord in an ovine model of fetal surgery for spina bifida. Surgery 144:367–373

    Article  PubMed  Google Scholar 

  21. Riess P, Zhang C, Saatman KE et al (2002) Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery 51:1043–1054

    PubMed  Google Scholar 

  22. Lubjuhn J, Gastens A, von Wilpert G et al (2009) Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery. J Neurosci Methods 184:95–103

    Article  PubMed  Google Scholar 

  23. Baskin YK, Dietrich WD, Green EJ (2003) Two effective behavioral tasks for evaluating sensorimotor dysfunction following traumatic brain injury in mice. J Neurosci Methods 129:87–93

    Article  PubMed  Google Scholar 

  24. Bermpohl D, You Z, Korsmeyer SJ et al (2006) Traumatic brain injury in mice deficient in bid: effects on histopathology and functional outcome. J Cereb Blood Flow Metab 26:625–633

    Article  PubMed  CAS  Google Scholar 

  25. Mothe AJ, Tator CH (2008) Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol 213:176–190

    Article  PubMed  CAS  Google Scholar 

  26. Zaheer A, Zhong W, Lim R (1995) Expression of mRNAs of multiple growth factors and receptors by neuronal cell lines: detection with RT-PCR. Neurochem Res 20:1457–1463

    Article  PubMed  CAS  Google Scholar 

  27. Benowitz LI, Routtenberg A (1997) GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci 20:84–91

    Article  PubMed  CAS  Google Scholar 

  28. Shear DA, Tate MC, Archer DR et al (2004) Neural progenitor cell transplants promote long-term functional recovery after traumatic brain injury. Brain Res 1026:11–22

    Article  PubMed  CAS  Google Scholar 

  29. Lennard PN, Kristen JA, Lyda MR et al (2004) Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci 5:41

    Article  Google Scholar 

  30. Lu P, Jones LL, Snyder EY et al (2003) Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181:115–129

    Article  PubMed  CAS  Google Scholar 

  31. Barnabé-Heider F, Miller FD (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 23:5149–5160

    PubMed  Google Scholar 

  32. Stanisz AM, Stanisz JA (2000) Nerve growth factor and neuroimmune interactions in inflammatory diseases. Ann NY Acad Sci 917:268–272

    Article  PubMed  CAS  Google Scholar 

  33. Ansari MA, Roberts KN, Scheff SW (2008) Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radic Biol Med 45:443–452

    Article  PubMed  CAS  Google Scholar 

  34. Valtorta F, Pennuto M, Bonanomi D et al (2004) Synaptophysin: leading actor or walk-on role in synaptic vesicle exocytosis? Bioessays 26:445–453

    Article  PubMed  CAS  Google Scholar 

  35. Tarsa L, Goda Y (2002) Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 99:1012–1016

    Article  PubMed  CAS  Google Scholar 

  36. Shojo H, Kibayashi K (2006) Changes in localization of synaptophysin following fluid percussion injury in the rat brain. Brain Res 1078:198–211

    Article  PubMed  CAS  Google Scholar 

  37. Boeckers TM, Bockmann J, Kreutz MR et al (2002) ProSAP/Shank proteins: a family of higher order organizing molecules of the post-synaptic density with an emerging role in human neurological disease. J Neurochem 81:903–910

    Article  PubMed  CAS  Google Scholar 

  38. Böckers TM, Mameza MG, Kreutz MR et al (2001) Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain shank protein family interact with the cytoskeletal protein alpha-fodrin. J Biol Chem 276:40104–40112

    Article  PubMed  Google Scholar 

  39. Liebau S, Vaida B, Storch A (2007) Maturation of synaptic contacts in differentiating neural stem cells. Stem Cells 25:1720–1729

    Article  PubMed  CAS  Google Scholar 

  40. Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

    Article  PubMed  CAS  Google Scholar 

  41. Ying Z, Roy RR, Zhong H et al (2008) BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience 155:1070–1078

    Article  PubMed  CAS  Google Scholar 

  42. Bamji SX, Rico B, Kimes N et al (2006) BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions. J Cell Biol 174:289–299

    Article  PubMed  CAS  Google Scholar 

  43. Jacobs KM, Neve RL, Donoghue JP (1993) Neocortex and hippocampus contain distinct distributions of calcium-calmodulin protein kinase II and GAP43 mRNA. J Comp Neurol 336:151–160

    Article  PubMed  CAS  Google Scholar 

  44. Hulsebosch CE, DeWitt DS, Jenkins LW et al (1998) Traumatic brain injury in rats results in increased expression of Gap-43 that correlates with behavioral recovery. Neurosci Lett 255:83–86

    Article  PubMed  CAS  Google Scholar 

  45. Fournier AE, Beer J, Arregui CO et al (1997) Brain-derived neurotrophic factor modulates GAP-43 but not T alpha1 expression in injured retinal ganglion cells of adult rats. J Neurosci Res 47:561–572

    Article  PubMed  CAS  Google Scholar 

  46. Klöcker N, Jung M, Stuermer CA et al (2001) BDNF Increases the number of axotomized rat retinal ganglion cells expressing GAP-43, L1, and TAG-1 mRNA: a supportive role for nitric oxide? Neurobiol Dis 8:103–113

    Article  PubMed  Google Scholar 

  47. Tobias CA, Shumsky JS, Shibata M et al (2003) Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration. Exp Neurol 184:97–113

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Professor Xuehu Ma from the Stem Cell and Tissue Engineering Laboratory of the Dalian University of Technology for his support in culturing the NSCs. This work was supported by grants No. 30850001 from the National Nature Science Foundation of China and Nos. 20072167, 2008779 and 2008851 from the S&T Research Project of Education Bureau, Liaoning Province, China.

Conflict of interest

The authors indicate no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Histology and Embryology and the Institute of Pathology and Pathophysiology, China Medical University, Shenyang, Liaoning, China

    Haiying Ma, Li Kong & Yuxiu Shi

  2. Shengjing Hospital Affiliated with China Medical University, Shenyang, Liaoning, China

    Bo Yu

  3. Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning, China

    Haiying Ma, Li Kong & Yuanyuan Zhang

  4. Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, 27157, USA

    Yuanyuan Zhang

Authors
  1. Haiying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuanyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuxiu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuxiu Shi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, H., Yu, B., Kong, L. et al. Neural Stem Cells Over-Expressing Brain-Derived Neurotrophic Factor (BDNF) Stimulate Synaptic Protein Expression and Promote Functional Recovery Following Transplantation in Rat Model of Traumatic Brain Injury. Neurochem Res 37, 69–83 (2012). https://doi.org/10.1007/s11064-011-0584-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0584-1

Keywords

Search

Navigation