Cellular and Molecular Neurobiology

, Volume 32, Issue 7, pp 1089–1097 | Cite as

Neurotrophin Expressions in Neural Stem Cells Grafted Acutely to Transected Spinal Cord of Adult Rats Linked to Functional Improvement

  • Ying-Li Gu
  • Lu-Wei Yin
  • Zhuo Zhang
  • Jia Liu
  • Su-Juan Liu
  • Lian-Feng Zhang
  • Ting-Hua WangEmail author
Original Research


It is well known that neural stem cells (NSC) could promote the repairment after spinal cord injury, but the underlying mechanism remains to be elucidated. This study showed that the transplantation of NSC significantly improved hindlimb locomotor functions in adult rats subjected to transection of the spinal cord. Biotin dextran amine tracing together with the stimulus experiment in motor sensory area showed that little CST regeneration existed and functional synaptic formation in the injury site. Immunocytochemistry and RT-PCR demonstrated the secretion of NGF, BDNF, and NT-3 by NSC in vitro and in vivo, respectively. However, only mRNA expression of BDNF and NT-3 but not NGF in injury segment following NSC transplantation was upregulated remarkably, while caspase-3, a crucial apoptosis gene, was downregulated simultaneously. These provided us a clue that the functional recovery was correlated with the regulation of BDNF, NT-3, and caspase-3 in spinal cord transected rats following NSC transplantation.


NSC Transplantation Sensory and locomotor functions Rat 



We thank Professor Seng-Kee Leong for his valuable comments on this manuscript. This research was supported by a grant from the China National Science Foundation (No. 30260125) and the New York-China Medical Board (CMB00-722).

Conflict of interest

We have no conflicts of interest in this study.


  1. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21PubMedCrossRefGoogle Scholar
  2. Blesch A, Lu P, Tuszynski MH (2002) Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull 57:833–838PubMedCrossRefGoogle Scholar
  3. Chen QY, Lu GH, Wu YQ, Zheng Y, Xu K, Wu LJ, Jiang ZY, Feng R, Zhou JY (2010) Curcumin induces mitochondria pathway mediated cell apoptosis in A549 lung adenocarcinoma cells. Oncol Rep 23:1285–1292PubMedGoogle Scholar
  4. Gao J, Coggeshall RE, Tarasenko YI, Wu P (2005) Human neural stem cell-derived cholinergic neurons innervate muscle in motoneuron deficient adult rats. Neuroscience 131:257–262PubMedCrossRefGoogle Scholar
  5. Himes BT, Liu Y, Solowska JM, Snyder EY, Fischer I, Tessler A (2001) Transplants of cells genetically modified to express neurotrophin-3 rescue axotomized Clarke’s nucleus neurons after spinal cord hemisection in adult rats. J Neurosci Res 65:549–564PubMedCrossRefGoogle Scholar
  6. Hu JL, Jiang XD, Zou YX, Guo YW, Zhou DX, Xu RX (2008) Culture and identification of neural stem cells derived from the subventricular zone of adult mice. Nan Fang Yi Ke Da Xue Xue Bao 28:1942–1946PubMedGoogle Scholar
  7. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736PubMedCrossRefGoogle Scholar
  8. Hung KS, Tsai SH, Lee TC, Lin JW, Chang CK, Chiu WT (2007) Gene transfer of insulin-like growth factor-I providing neuroprotection after spinal cord injury in rats. J Neurosurg Spine 6:35–46PubMedCrossRefGoogle Scholar
  9. Isackson PJ (1995) Trophic factor response to neuronal stimuli or injury. Curr Opin Neurobiol 5:350–357PubMedCrossRefGoogle Scholar
  10. Kalyani A, Hobson K, Rao MS (1997) Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis. Dev Biol 186:202–223PubMedCrossRefGoogle Scholar
  11. 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) 32:1272CrossRefGoogle Scholar
  12. Klapka N, Hermanns S, Straten G, Masanneck C, Duis S, Hamers FP, Müller D, Zuschratter W, Müller HW (2005) Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. Eur J Neurosci 22:3047–3058PubMedCrossRefGoogle Scholar
  13. Li SH, Hou TS (2001) The impact of direct-current stimulation on apoptotic adjustable gene expression of spinal cord motorneurons after sciatic nerve transection. Chin J Traumatol 17:398–401Google Scholar
  14. Li N, Liu GT (2010) The novel squamosamide derivative, FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice. Acta Pharmacol Sin 31:265–272PubMedCrossRefGoogle Scholar
  15. Li XL, Zhang W, Zhou X, Wang XY, Zhang HT, Qin DX, Zhang H, Li Q, Li M, Wang TH (2007) Temporal changes in the expression of some neurotrophins in spinal cord transected adult rats. Neuropeptides 41:135–143PubMedCrossRefGoogle Scholar
  16. Lou J, Lenke LG, Xu F, O’Brien M (1998) In vivo Bcl-2 oncogene neuronal expression in the rat spinal cord. Spine 23:517–523PubMedCrossRefGoogle Scholar
  17. Lu P, Jones LL, Snyder EY, Tuszynski MH (2003) Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181:115PubMedCrossRefGoogle Scholar
  18. Lu P, Jones LL, Tuszynski MH (2005) BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191:344–360PubMedCrossRefGoogle Scholar
  19. Mayer-Proschel M, Kalyani AJ, Mujtaba T, Rao MS (1997) Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19:773–785PubMedCrossRefGoogle Scholar
  20. McAllister AK, Katz LC, Lo DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22:295–318PubMedCrossRefGoogle Scholar
  21. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:1410–1412PubMedCrossRefGoogle Scholar
  22. Okano H (2000) Neural stem cells: the basic biology and prospects for brain repair. Nihon Shinkei Seishin Yakurigaku Zasshi 20:21–26PubMedGoogle Scholar
  23. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619PubMedCrossRefGoogle Scholar
  24. Ostenfeld T, Svendsen CN (2003) Recent advances in cell neurobiology. Adv Tech Stand Neurosurg 28:3–89PubMedCrossRefGoogle Scholar
  25. Sendtner M, Pei G, Beck M, Schweizer U, Wiese S (2000) Developmental motoneuron cell death and neurotrophic factors. Cell Tissue Res 301:71–84PubMedCrossRefGoogle Scholar
  26. Singh RP, Shiue K, Schomberg D, Zhou FC (2009) Cellular epigenetic modifications of neural stem cell differentiation. Cell Transplant 18:1197–1211PubMedCrossRefGoogle Scholar
  27. Sun Y, Shi J, Fu SL, Lu PH, Xu XM (2003) Effects of embryonic neural stem cells and glial cell line-derived neurotrophic factor in the repair of spinal cord injury. Sheng Li Xue Bao 55:349–354PubMedGoogle Scholar
  28. Tarasenko YI, Gao J, Nie L, Johnson KM, Grady JJ, Hulsebosch CE, McAdoo DJ, Wu P (2007) Human fetal neural stem cells grafted into contusion-injured rat spinal cords improve behavior. J Neurosci Res 85:47–57PubMedCrossRefGoogle Scholar
  29. Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF, van der Kooy D (1999) Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208:166–188PubMedCrossRefGoogle Scholar
  30. Tuszynski MH, Grill R, Leonard L (2003) NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Exp Neurol 181:47–56PubMedCrossRefGoogle Scholar
  31. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97:14720–14725PubMedCrossRefGoogle Scholar
  32. Vroemen M, Aigner L, Winkler J, Weidner N (2003) Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18:743–775PubMedCrossRefGoogle Scholar
  33. Wei P, Liu J, Zhou HL, Han ZT, Wu QY, Pang JX, Liu S, Wang TH (2007) Effects of engrafted neural stem cells derived from GFP transgenic mice in Parkinson’s diseases rats. Neurosci Lett 419:49–54PubMedCrossRefGoogle Scholar
  34. Xie YB, Niu YJ, Yuan CY, Ying Y, Yu YT (2007) Effects of BDNF on the expression of caspase-2 and caspase-3 and cell apoptosis in retinal ischemia/reperfusion injury. Int J Ophthalmol 7:1217–1221Google Scholar
  35. Zhang L, Gu S, Zhao C, Wen T (2007) Combined treatment of neurotrophin-3 gene and neural stem cells is propitious to functional recovery after spinal cord injury. Cell Transplant 16:475–481PubMedGoogle Scholar
  36. Zhao Q, Gao J, Li W, Cai D (2010) Neurotrophic and neurorescue effects of echinacoside in the subacute MPTP mouse model of Parkinson’s disease. Brain Res 1346:224–236PubMedCrossRefGoogle Scholar
  37. Zhou HL, Yang HJ, Li YM, Wang Y, Yan L, Guo XL, Ba YC, Liu S, Wang TH (2008) Changes in glial cell line-derived neurotrophic factor expression in the rostral and caudal stumps of the transected adult rat spinal cord. Neurochem Res 33:927–937PubMedCrossRefGoogle Scholar
  38. Zhou X, Yang JW, Zhang W, Ou KQ, Zhou HL, Ma YQ, Chen SX, Li LY, Wang TH (2009) Role of NGF in spared DRG following partial dorsal rhizotomy in cats. Neuropeptides 43:363–369PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ying-Li Gu
    • 1
  • Lu-Wei Yin
    • 2
  • Zhuo Zhang
    • 5
  • Jia Liu
    • 2
  • Su-Juan Liu
    • 4
  • Lian-Feng Zhang
    • 3
  • Ting-Hua Wang
    • 2
    • 4
    Email author
  1. 1.Department of Neurology, West China HospitalSichuan UniversityChengduChina
  2. 2.Institute of Neuroscience, Kunming Medical CollegeKunmingChina
  3. 3.Institute of Laboratory Animal ScienceCAMSBeijingChina
  4. 4.Translational Neuroscience CenterInstitute of Neurological Disease, West China Hospital, Sichuan UniversityChengduChina
  5. 5.Department of NeurologyTangdu Hospital, Fourth Military Medical UniversityXi’anChina

Personalised recommendations