Journal of Molecular Neuroscience

, Volume 49, Issue 2, pp 409–416 | Cite as

Protective Effects of BDNF Overexpression Bone Marrow Stromal Cell Transplantation in Rat Models of Traumatic Brain Injury

  • Zhitao Wang
  • Weifeng Yao
  • Quanjun Deng
  • Xiaohui Zhang
  • Jianning ZhangEmail author


Bone marrow stromal cells (MSCs) were used as cell therapy for various diseases in recent years. Some reports showed that transplanted MSCs promote functional recovery in animal models of brain trauma. But other studies indicate that tissue replacement by this method may not be the main source of therapeutic benefit. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) therapeutic potential may contribute to the recovery of function after trauma. Our previous study showed that BDNF–MSCs could promote the survival of neurons in neuronal injured models in vitro. The present study was undertaken to explore the therapeutic effects of MSCs transfected with BDNF in vivo. After intraventricular injection of MSCs–BDNF, BDNF levels were increased significantly in cerebrospinal fluid by ELISA. Further studies showed that treatment of traumatic brain injury with MSCs–BDNF could attenuate neuronal injury as measurement of biological behavior assessment. These studies demonstrate that by increasing the brain concentration of BDNF, intraventricularly transplanted MSCs–BDNF might play an important role in the treatment of traumatic brain injury and might be an optional therapeutic strategy.


Marrow stromal cells Brain-derived neurotrophic factor Traumatic brain injury 


  1. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N et al (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction. Circulation 106:3009–3017PubMedCrossRefGoogle Scholar
  2. Beni-Adani L, Gozes I, Cohen Y, Assaf Y, Steingart RA, Brenneman DE, Eizenberg O, Trembolver V, Shohami E. (2001). A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther. 296.57-63.Google Scholar
  3. Böker W, Yin Z, Drosse I, Haasters F, Rossmann O, Wierer M et al (2008) Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer. J Cell Mol Med 12:1347–1359PubMedCrossRefGoogle Scholar
  4. Bolton MM, Pittman AJ, Lo DC (2000) Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 20:3221–3232PubMedGoogle Scholar
  5. Borlongan CV, Stahl CE, Cameron DF, Saporta S, Freeman TB, Cahill DW et al (1996) CNS immunological modulation of neural graft rejection and survival. Neurol Res 18:297–304PubMedGoogle Scholar
  6. Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779PubMedCrossRefGoogle Scholar
  7. Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M (2001a) Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189:49–57CrossRefGoogle Scholar
  8. Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J et al (2001b) Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology 22:275–279CrossRefGoogle Scholar
  9. Chen X, Katakowski M, Li Y, Lu D, Wang L, Zhang L et al (2002) Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 69:687–691PubMedCrossRefGoogle Scholar
  10. Cheng SL, Yang JW, Rifas L, Zhang SF, Avioli LV (1994) Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone. Endocrinology 134:277–286PubMedCrossRefGoogle Scholar
  11. Chiaretti A, Piastra M, Polidori G (2003) Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury. Intensive Care Med 29:1329–1338PubMedCrossRefGoogle Scholar
  12. Clark BR, Keating A (1995) Biology of bone marrow stroma. Ann N Y Acad Sci 770:70–78PubMedCrossRefGoogle Scholar
  13. Desai NS, Rutherford LC, Turrigiano GG (1999) Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nat Neurosci 2:515–520PubMedCrossRefGoogle Scholar
  14. Diógenes MJ, Costenla AR, Lopes LV (2011) Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology 36:1823–1836PubMedCrossRefGoogle Scholar
  15. Dixon CE, Flinn P, Bao J, Venya R, Hayes RL (1997) Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats. Exp Neurol 146:479–490PubMedCrossRefGoogle Scholar
  16. Fleming JO, Ting JYP, Stohlman SA, Weiner LP (1983) Improvements in obtaining and characterizing mouse cerebrospinal fluid. Application to mouse hepatitis virus-induced encephalomyelitis J Neuroimmunol 4:129–140Google Scholar
  17. Hariri AR, Goldberg TE, Mattay VS (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690–6694PubMedGoogle Scholar
  18. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M et al (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313PubMedCrossRefGoogle Scholar
  19. Jendelová P, Herynek V, DeCroos J, Glogarová K, Andersson B, Hájek M et al (2003) Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles. Magn Reson Med 50:767–776PubMedCrossRefGoogle Scholar
  20. Kang H, Schuman EM (1996) A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273:1402–1406PubMedCrossRefGoogle Scholar
  21. 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 21:427–437PubMedCrossRefGoogle Scholar
  22. Kim HJ, Lee JH, Kim SH (2010) Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. J Neurotrauma 27:131–138PubMedCrossRefGoogle Scholar
  23. Koç ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI et al (2000) Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 18:307–316PubMedGoogle Scholar
  24. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J et al (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436PubMedCrossRefGoogle Scholar
  25. Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX et al (2000) Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:1311–1319PubMedCrossRefGoogle Scholar
  26. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX et al (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523PubMedCrossRefGoogle Scholar
  27. Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143PubMedCrossRefGoogle Scholar
  28. Lu D, Li Y, Mahmood A, Wang L, Rafiq T, Chopp M (2002) Neural and marrow-derived stromal cell sphere transplantation in a rat model of traumatic brain injury. J Neurosurg 97:935–940PubMedCrossRefGoogle Scholar
  29. Mahmood A, Lu D, Wang L, Li Y, Lu M, Chopp M (2001a) Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 49:1196–1203PubMedGoogle Scholar
  30. Mahmood A, Lu D, Yi L, Chen JL, Chopp M (2001b) Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats. J Neurosurg 94:589–595PubMedCrossRefGoogle Scholar
  31. Mahmood A, Lu D, Wang L, Chopp M (2002) Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. J Neurotrauma 19:1609–1617PubMedCrossRefGoogle Scholar
  32. McIntosh TK, Smith DH, Meaney DF, Kotapka MJ, Gennarelli TA, Graham DI (1996) Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. Lab Invest 74:315–342PubMedGoogle Scholar
  33. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (2000) Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779–1782PubMedCrossRefGoogle Scholar
  34. Mori T, Kiyono T, Imabayashi H, Takeda Y, Tsuchiya K, Miyoshi S et al (2005) Combination of hTERT and bmi-1, E6, or E7 induces prolongation of the life span of bone marrow stromal cells from an elderly donor without affecting their neurogenic potential. Mol Cell Biol 25:5183–5195PubMedCrossRefGoogle Scholar
  35. Mu JS, Li WP, Yao ZB, Zhou XF (1999) Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 835:259–265PubMedCrossRefGoogle Scholar
  36. Philips MF, Mattiasson G, Wieloch T, Bjorklund A, Johansson BB, Tomasevic G et al (2001) Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury. J Neurosurgs 94:765–774CrossRefGoogle Scholar
  37. Sinson G, Perri BR, Trojanowski JQ, Flamm ES, McIntosh TK (1997) Improvement of cognitive deficits and decreased cholinergic neuronal cell loss and apoptotic cell death following neurotrophin infusion after experimental traumatic brain injury. J Neurosurg 86:511–518PubMedCrossRefGoogle Scholar
  38. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedCrossRefGoogle Scholar
  39. Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598PubMedCrossRefGoogle Scholar
  40. Wang Z, Deng Q, Zhang X et al (2009) Treatment of injured neurons with bone marrow stem cells cotransfected by hTERT and Ad-BDNF in vitro. J Mol Neurosci 38:265–272PubMedCrossRefGoogle Scholar
  41. Williams LR, Varon S, Peterson GM, Wictorin K, Fischer W, Bjorklund A et al (1986) Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc Natl Acad Sci USA 83:9231–9235PubMedCrossRefGoogle Scholar
  42. Yang K, Perez-Polo JR, Mu XS (1996) Increased expression of brain-derived neurotrophic factor but not neurotrophin-3 mRNA in rat brain after cortical impact injury. J Neurosci Res 44:157–164PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Zhitao Wang
    • 1
    • 2
    • 3
    • 4
  • Weifeng Yao
    • 5
  • Quanjun Deng
    • 6
  • Xiaohui Zhang
    • 7
  • Jianning Zhang
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of NeurosurgeryTianjin Medical University General HospitalTianjinPeople’s Republic of China
  2. 2.Tianjin Neurologic InstituteTianjinPeople’s Republic of China
  3. 3.Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of EducationTianjinPeople’s Republic of China
  4. 4.Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous SystemTianjinPeople’s Republic of China
  5. 5.Tianjin Academy of Traditional Chinese Medicine Affiliated HospitalTianjinPeople’s Republic of China
  6. 6.Department of NeurosurgeryTianjin Huanghe Road HospitalTianjinPeople’s Republic of China
  7. 7.Department of NeurosurgeryTianjin Medical University Cancer Institute and HospitalTianjinPeople’s Republic of China

Personalised recommendations