Document Type : Original Article

Authors

1 Assistant Professor, Hearing Disorders Research Center & Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Professor, Department of Anatomical Science, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran and Shefa Neuroscience Research Center, Khatam Al-Anbia Hospital, Tehran, Iran

3 Professor, Department of Genetics, Faculty of Sciences, Tarbiat Modares University, Tehran, Iran

4 Associate Professor, Department of Anatomical Science, School of Medical Science, Shahed University, Tehran, Iran

5 Shefa Neuroscience Research Center, Khatam Al-Anbia Hospital, Tehran, Iran

6 Professor, Hearing Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Abstract Background & Aims: Cell therapy is among the novel therapeutic methods effective in the treatment of spinal cord injuries. The aim of the present study was using neural stem cells (NSCs) in treating contusion spinal cord injury in rat model.
Methods: Bone marrow stromal cells (BMSCs) were isolated from adult rats. After three passages, these cells were transdifferntiated to neurospheres and subsequently to neural stem cells (NSCs). At in vivo studies, 43 adult female rats were divided into 5 groups. For the first group or Sham, laminectomy was the only procedure performed, whereas for the other four groups, after laminectomy, a contusion Spinal Cord Injury (SCI) was induced, as well. In group 2, no treatment was performed. In the other groups, injection was performed 7 days after SCI, as such: in groups 3, 4, and 5 normal saline, BMSCs, and NSCs were injected, respectively. The injections were administered intraspinally (IS). Motor improvement was assessed via BBB test one day before SCI and continued up to 12 weeks afterwards in all groups.
Results: The current study revealed that a considerable percentage of the cells were BMSCs after the fourth passage. These cells were then transformed into neurospheres and NSCs. In all the experimental cell-therapy groups, a significant motor improvement was observed in comparison with that in the control group. This healing was more obvious during the period between the 2nd and the 4th weeks and less prominent during the period between the 4th and the 12th weeks.
Conclusion: Transplantation of NSCs leads to partial motor improvement in contusive rat models.

Keywords

  1. Donnelly EM, Lamanna J, Boulis NM.Stem cell therapy for the spinal cord. Stem Cell Res Ther 2012; 3(4):24.
  2. Anderson AJ, Robert S, Huang W, Young W, Cotman CW. Activation of complement pathways after contusion-induced spinal cord injury. J Neurotrauma 2004; 21(12):1831-46.
  3. Wright KT, El-Masri W, Osman A, Chowdhury J, Johnson WE. Concise review: Bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications. Stem Cells 2011; 29(2):169-78.
  4. Rabchevsky AG, Streit WJ. Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res 1997; 47(1):34-48.
  5. Li W, Maeda Y, Ming X, Cook S, Chapin J, Husar W, Dowling P. Apoptotic death following fas activation in human oligodendrocyte hybrid cultures. J Neurosci Res 2002; 69(2): 189–196.
  6. Abbaszadeh HA, Tiraihi T, Delshad AR, SadeghiZadeh M Taheri, T. Bone marrow stromal cell transdifferentiation into oligodendrocyte-like cells using triiodothyronine as a inducer with expression of platelet-derived growth factor α as a maturity marker. Iran Biomed j 2013; 17(2): 62-70.
  7. Ronaghi M, Erceg S, Moreno-Manzano V, Stojkovic M. Challenges of stem cell therapy for spinal cord injury: human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells. Stem Cells 2010; 28(1):93-9.
  8. Chen MS, Huber AB, van der Harr ME, Frank M, Schnell L, Spillmann AA, et al. Nogo-A is a myelin associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 2000; 403: 434-9.
  9. Xue M, Hollenberg MD, Yong VW. Combination of Thrombin and Matrix Metalloproteinase-9 Exacerbates Neurotoxicity in Cell Culture and Intracerebral hemorrhage in mice. J Neurosci 2006; 26(40): 10281-91
  10. Zhang N, Yan H, Wen X. Tissue-engineering approaches for axonal guidance. Brain Res Brain Rev 2005; 49(1):48-64.
  11. Hou SY, Zhang HY, Quan DP, Liu XL, Zhu JK. Tissue-engineered peripheral nerve grafting by differentiated bone marrow stromal cells. Neuroscience 2006; 140(1):101-10.
  12. Marshall GP, Reynolds BA, Laywell ED. sings the neurosphere assay to quantify neural stem cells in vivo. Curr Pharm Biotechnol. 2007 Jun; 8(3):141-5.
  13. Darabi S, Tiraihi T, Ruintan A, Abbaszadeh HA, Delshad A, Taheri T.Polarized neural stem cells derived from adult bone marrow stromal cells develop a rosette-like structure. In Vitro Cell Dev Biol Anim 2013; 49(8): 638-
  14. Kaka GR, Tiraihi T, Delshad A, Arabkheradmand J, Kazemi H. In vitro differentiation of bone marrow stromal cells into oligodendrocyte-like cells using triiodothyronine as inducer. Int J Neurosci. 2012 May; 122(5):237-47.
  15. Deng W1, Obrocka M, Fischer I, Prockop DJ. In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun. 2001 Mar 23; 282(1):148-52.
  16. Darabi S, Tiraihi T, Delshad A, Sadeghizadeh M. A new multistep induction protocol for the transdifferentiation of bone marrow stromal stem cells into GABAergic neuron-like cells. Iran Biomed J. 2013; 17(1):8-14.
  17. Abbaszadeh HA, Tiraihi T, Delshad A, Saghedizadeh M, Taheri T, Kazemi H. Differentiation of neurosphere-derived rat neural stem cells into oligodendrocyte-like cells by repressing PDGF-α and Olig2 with triiodothyronine. Tissue Cell 2014; 46(6): 462-9.
  18. Gharibani PM, Tiraihi T, Arabkheradmand J. In vitro differentiation of GABAergic cells from bone marrow stromal cells using potassium chloride as inducer. Restor Neurol Neurosci. 2010;28(3):367-77
  19. Kuhn HG, Palmer TD, Fuchs T. Adult neurogenesis: a compensatory mechanism for neuronal damage. Eur Arch Psychiatry Clin Neurosci 2001; 251(4):152-8.
  20. Ankeny D.P. McTigue D.M. Jakeman L.B. Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats. Exp. Neurol. 2004; 190:17-31.
  21. Abbaszadeh HA, Tiraihi T, Noori-Zadeh A, Delshad AR, Sadeghizade M, Taheri T. Human ciliary neurotrophic factor–overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury. Cytotherapy 2015; 17(7): 912-21.
  22. Cloutier F, Siegenthaler MM, Nistor G, Keirstead HS.Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm. Regen Med. 2006 Jul; 1(4):469-79.
  23. Ankeny DP, McTigue DM, Guan Z, Yan Q, Kinstler O, Stokes BT, Jakeman LB. Pegylated brain-derived neurotrophic factor shows improved distribution into the spinal cord and stimulates locomotor activity and morphological changes after injury. Exp Neurol. 2001 Jul; 170(1):85-100.
  24. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005 May 11; 25(19):4694-705.