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Neural Stem Cells Grafts Decrease Neural Apoptosis Associated with Caspase-7 Downregulation and BDNF Upregulation in Rats Following Spinal Cord Hemisection

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Abstract

Transplantation of neural stem cells (NSCs) into lesioned spinal cord demonstrated a beneficial effect for neural repair, the underlying mechanism, however, remains to be elusive. Here, we showed that NSCs, possessing the capacity to differentiate toward into neurons and astrocytes, exhibit a neuroprotective effect by anti-apoptosis mechanism in spinal cord hemi-transected rats despite it did not improve behavior. Intravenous NSCs injection substantially upregulated the level of BDNF mRNA but not its receptor TrkB in hemisected spinal cord, while caspase-7, a downstream apoptosis gene of caspase-3, has been largely down-regulated. TUNEL staining showed that the number of apoptosis cells in injured spinal cord decreased significantly, compared with seen in rats with no NSCs administration. The present finding therefore provided crucial evidence to explain neuroprotective effect of NSCs grafts in hemisected spinal cord, which is associated with BDNF upregulation and caspase-7 downregulation.

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References

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

    Article  PubMed  CAS  Google Scholar 

  • Blesch A, Lu P, Tuszynski MH (2002) Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull 57:833–838

    Article  PubMed  CAS  Google Scholar 

  • Bottai D, Madaschi L, Di Giulio AM, Gorio A (2008) Viability-dependent promoting action of adult neural precursors in spinal cord injury. Mol Med 14:634–644

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Hu YR, Wan H, Xia L, Li JH, Yang F, Qu X, Wang SG, Wang ZC (2010) Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells and Schwann cells. Chin Med J (Engl) 123:2424–2431

    CAS  Google Scholar 

  • Enomoto M, Shinomiya K, Okabe S (2003) Migration and differentiation of neural progenitor cells from two different regions of embryonic central nervous system after transplantation into the intact spinal cord. Eur J Neurosci 17:1223–1232

    Article  PubMed  Google Scholar 

  • Fauza DO, Jennings RW, Teng YD, Snyder EY (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 

  • Foret A, Quertainmont R, Botman O, Bouhy D, Amabili P, Brook G, Schoenen J, Franzen R (2010) Stem cells in the adult rat spinal cord: plasticity after injury and treadmill training exercise. J Neurochem 112:762–772

    Article  PubMed  CAS  Google Scholar 

  • Gu YL, Yin LW, Zhang Z, Liu J, Liu SJ, Zhang LF, Wang TH (2012) Neurotrophin expressions in neural stem cells grafted acutely to transected spinal cord of adult rats linked to functional improvement. Cell Mol Neurobiol 32:1089–1097

    Article  PubMed  CAS  Google Scholar 

  • Harada N, Ito N, Nagai T, Sanagi T, Yamada H (2010) Ferulic acid induces neural progenitor cell proliferation in vitro and in vivo. Neuroscience 165:515–524

    Article  PubMed  Google Scholar 

  • Hasegawa K, Chang YW, Li H, Berlin Y, Ikeda O, Kane-Goldsmith N, Grumet M (2005) Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury. Exp Neurol 193:394–410

    Article  PubMed  CAS  Google Scholar 

  • He BL, Ba YC, Wang XY, Liu SJ, Liu GD, Ou S, Gu YL, Pan XH, Wang TH (2013) BDNF expression with functional improvement in transected spinal cord treated with neural stem cells in adult rats. Neuropeptides 47(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Horky LL, Galimi F, Gage FH, Horner PJ (2006) Fate of endogenous stem/progenitor cells following spinal cord injury. J Comp Neurol 498:525–538

    Article  PubMed  Google Scholar 

  • Hwang DH, Kim BG, Kim EJ, Lee SI, Joo IS, Suh-Kim H, Sohn S, Kim SU (2009) Transplantation of human neural stem cells transduced with Olig2 transcription factor improves locomotor recovery and enhances myelination in the white matter of rat spinal cord following contusive injury. BMC Neurosci 10:117

    Article  PubMed  Google Scholar 

  • Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM, McKay RD (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10:3129–3140

    Article  PubMed  CAS  Google Scholar 

  • Karimi-Abdolrezaee S, Billakanti R (2012) Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol 46:251–264

    Article  PubMed  CAS  Google Scholar 

  • Kim HM, Hwang DH, Lee JE, Kim SU, Kim BG (2009) Ex vivo VEGF delivery by neural stem cells enhances proliferation of glial progenitors, angiogenesis, and tissue sparing after spinal cord injury. PLoS One 4:e4987

    Article  PubMed  Google Scholar 

  • Lee SH, Chung YN, Kim YH, Kim YJ, Park JP, Kwon DK, Kwon OS, Heo JH, Kim YH, Ryu S, Kang HJ, Paek SH, Wang KC, Kim SU, Yoon BW (2009) Effects of human neural stem cell transplantation in canine spinal cord hemisection. Neurol Res 31:996–1002

    Article  PubMed  Google Scholar 

  • Liu F, Zou Y, Liu SJ, Liu J, Wang TH (2013). Electro-acupuncture treatment improves neurological function associated with downregulation of PDGF and inhibition of astrogliosis in rats with spinal cord transaction. J Mol Neurosci. Pubmed ahead

  • 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 181:115–129

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • McLeod M, Hong M, Sen A, Sadi D, Ulalia R, Behie LA, Mendez I (2006) Transplantation of bioreactor-produced neural stem cells into the rodent brain. Cell Transplant 15:689–697

    Article  PubMed  CAS  Google Scholar 

  • Mitrecić D, Nicaise C, Gajović S, Pochet R (2010) Distribution, differentiation, and survival of intravenously administered neural stem cells in a rat model of amyotrophic lateral sclerosis. Cell Transplant 19:537–548

    Article  PubMed  Google Scholar 

  • Mueller AM, Pedré X, Stempfl T, Kleiter I, Couillard-Despres S, Aigner L, Giegerich G, Steinbrecher A (2008) Novel role for SLPI in MOG-induced EAE revealed by spinal cord expression analysis. J Neuroinflammation 5:20

    Article  PubMed  Google Scholar 

  • Nakamura M, Toyama Y, Okano H (2005) Transplantation of neural stem cells for spinal cord injury. Rinsho Shinkeigaku 45:874–876

    PubMed  Google Scholar 

  • Nicaise C, Mitrecic D, Pochet R (2011) Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells. Neuropathol Appl Neurobiol 37:179–188

    Article  PubMed  CAS  Google Scholar 

  • Niu C, Yip HK (2011) Neuroprotective signaling mechanisms of telomerase are regulated by brain-derived neurotrophic factor in rat spinal cord motor neurons. J Neuropathol Exp Neurol 70:634–652

    Article  PubMed  CAS  Google Scholar 

  • Olson HE, Rooney GE, Gross L, Nesbitt JJ, Galvin KE, Knight A, Chen B, Yaszemski MJ, Windebank AJ (2009) Neural stem cell and Schwann cell-loaded biodegradable polymer scaffolds support axonal regeneration in the transected spinal cord. Tissue Eng Part A 15:1797–1805

    Article  PubMed  CAS  Google Scholar 

  • Park H, Poo MM (2012) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14:7–23

    Article  Google Scholar 

  • Rizzardini M, Lupi M, Bernasconi S, Mangolini A, Cantoni L (2003) Mitochondrial dysfunction and death in motor neurons exposed to the glutathione-depleting agent ethacrynic acid. J Neurol Sci 207:51–58

    Article  PubMed  CAS  Google Scholar 

  • Schwerdtfeger K, Mautes AE, Bernreuther C, Cui Y, Manville J, Dihné M, Blank S, Schachner M (2012) Stress-resistant neural stem cells positively influence regional energy metabolism after spinal cord injury in mice. J Mol Neurosci 46:401–409

    Article  PubMed  CAS  Google Scholar 

  • Setoguchi T, Kondo T (2004) Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. J Cell Biol 166:963–968

    Article  PubMed  CAS  Google Scholar 

  • Shen Y, Xu J, Xu W, Xu L, Lu J, Gu Y (2008) Experimental study on neural stem cell transplantation delaying denervated muscle atrophy. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 22(9):1051–1055

    PubMed  Google Scholar 

  • Takeuchi H, Natsume A, Wakabayashi T, Aoshima C, Shimato S, Ito M, Ishii J, Maeda Y, Hara M, Kim SU, Yoshida J (2007) Intravenously transplanted human neural stem cells migrate to the injured spinal cord in adult mice in an SDF-1- and HGF-dependent manner. Neurosci Lett 426(2):69–74

    Article  PubMed  CAS  Google Scholar 

  • Teng YD, Yu D, Ropper AE, Li J, Kabatas S, Wakeman DR, Wang J, Sullivan MP, Redmond DE Jr, Langer R, Snyder EY, Sidman RL (2011) Function multipotency of stem cells: a conceptual review of neurotrophic factor-based evidence and its role in translational research. Curr Neuropharmacol 9:574–585

    Article  PubMed  CAS  Google Scholar 

  • Walker PA, Harting MT, Jimenez F, Shah SK, Pati S, Dash PK, Cox CS Jr (2010) Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NF kappaB-mediated increase in interleukin-6 production. Stem Cells Dev 19:867–876

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Kisaalita WS (2011) Administration of BDNF/ginsenosides combination enhanced synaptic development in human neural stem cells. J Neurosci Methods 194:274–282

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Dan QQ, Li Y (2010). Expression of PDGF, EGF and GDNF in cultured NSCs of mice in vitro. J Kunming Medical University 11:13–16

    Google Scholar 

  • Wang JM, Zeng YS, Wu JL, Li Y, Teng YD (2011) Cograft of neural stem cells and schwann cells overexpressing TrkC and neurotrophin-3 respectively after rat spinal cord transection. Biomaterials 32:7454–7468

    Article  PubMed  CAS  Google Scholar 

  • Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE (2009) Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J Comp Neurol 514:297–309

    Article  PubMed  CAS  Google Scholar 

  • Yan J, Welsh AM, Bora SH, Snyder EY, Koliatsos VE (2004) Differentiation and tropic/trophic effects of exogenous neural precursors in the adult spinal cord. J Comp Neurol 480:101–114

    Article  PubMed  Google Scholar 

  • Zhang J, Zhao F, Wu G, Li Y, Jin X (2010) Functional and histological improvement of the injured spinal cord following transplantation of Schwann cells transfected with NRG1 gene. Anat Rec (Hoboken) 293:1933–1946

    Article  Google Scholar 

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Correspondence to Ting-hua Wang or Jian-guo Qi.

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Guan-nan Xia, Yu Zou, Ting-hua Wang, and Jian-guo Qi contributed equally to this study.

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Xia, Gn., Zou, Y., Wang, Yc. et al. Neural Stem Cells Grafts Decrease Neural Apoptosis Associated with Caspase-7 Downregulation and BDNF Upregulation in Rats Following Spinal Cord Hemisection. Cell Mol Neurobiol 33, 1013–1022 (2013). https://doi.org/10.1007/s10571-013-9969-9

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  • DOI: https://doi.org/10.1007/s10571-013-9969-9

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