Stem Cells: New Hope For Spinal Cord Injury

Open access


Stem cell therapy offers several attractive strategies for spinal cord repair. The regenerative potential of pluripotent stem cells was confirmed in an animal model of Spinal Cord Injury (SCI); nevertheless, optimized growth and differentiation protocols along with reliable safety assays should be established prior to the clinical application of hESCs and iPSCs. Th e therapeutic effects of mesenchymal stem cells (MSCs) in SCI result from neurotrophin secretion, angiogenesis, and antiinflammatory actions. Several preclinical SCI studies have reported that the occurrence of axonal extension, remyelination and neuroprotection occur after the transplantation of olfactory ensheathing cells (OECs). The transplantation of neural stem cells NSCs (NSCs) promotes partial functional improvement after SCI because of their potential to differentiate into neurons, oligodendrocytes, and astrocytes. The ideal source of stem cells for safe and efficient cell-based therapy for SCI remains a challenging issue that requires further investigation.

1. Volarevic V, Erceg S, Bhattacharya SS, Stojkovic P, Horner P, Stojkovic M. Stem Cell-Based Therapy for Spinal Cord Injury. Cell Transplantation 2013; 22(8):1309-23.

2. Lukovic D, Moreno Manzano V, Stojkovic M, Bhattacharya SS, Erceg S. Concise review: human pluripotent stem cells in the treatment of spinal cord injury. Stem Cells 2012; 30(9):1787-92.

3. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: Promise on the horizon. Neurosurg. Focus 2008; 25:E2.

4. McTigue DM, Tani M, Krivacic K et al. Selective chemokine mRNA accumulation in the rat spinal cord after contusion injury. J Neurosci Res 1998;53:368–376.

5. Grossman SD, Rosenberg LJ, Wrathall JR. Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp Neurol 2001;168:273–282.

6. Erceg S, Ronaghi M, Stojković M. Human embryonic stem cell differentiation toward regional specific neural precursors. Stem Cells 2009. 27(1):78-87.

7. Erceg S, Ronaghi M, Oria M, et al. Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells 2010; 28:1541–1549.

8. Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 2005; 49:385–396.

9. Mothe AJ, Tator CH. Advances in stem cell therapy for spinal cord injury. J Clin Invest. 2012; 122(11):3824-34.

10. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–676.

11. Lukovic D, Moreno-Manzano V, Klabusay M, Stojkovic M, Bhattacharya SS, Erceg S. Non-coding RNAs in pluripotency and neural differentiation of human pluripotent stem cells. Front Genet. 2014; 14;5:132.

12. Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010; 7:618–630.

13. Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem cell 2009; 4:381–384.

14. Tsuji O, Miura K, Okada Y, et al. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 2010; 107:12704–12709.

15. Nori S, Okada Y, Yasuda A, et al. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci USA 2011;108: 16825–16830.

16. Volarevic V, Al-Qahtani A, Arsenijevic N, et al. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity 2010; 43: 255–63.

17. Hawryluk GW, Mothe AJ, Chamankhah M, Wang J, Tator C, Fehlings MG. In vitro characterization of trophic factor expression in neural precursor cells. Stem Cells Dev. 2012; 21(3):432–447.

18. Himes BT, Neuhuber B, Coleman C et al. Recovery of function following grafting of human bone marrowderived stromal cells into the injured spinal cord. Neurorehabil Neural Repair 2006; 20(2):278–296.

19. Hawryluk GW, Mothe A, Wang J, Wang S, Tator C, Fehlings MG. An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells Dev. 2012; 21(12):2222–2238.

20. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006; 98(5):1076–1084.

21. Ruff CA, Wilcox JT, Fehlings MG. Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp. Neurol. 2012; 235:78–90.

22. Kim HJ, Lee HJ, Kim SH. Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: Secretion of neurotrophic factors and inhibition of apoptosis. J. Neurotrauma 2010; 27:131–138.

23. Sasaki M, Radtke C, Tan AM, et al. BDNF hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. J. Neurosci. 2009; 29:14932–14941.

24. Martinez AM, Goulart CO, Ramalho Bdos S, Oliveira JT, Almeida FM. Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials. World J Stem Cells 2014; 6(2):179-94.

25. Li J, Lepski G. Cell transplantation for spinal cord injury: a systematic review. Biomed Res Int. 2013; 2013:786475.

26. Syková E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006; 15:675–687.

27. Yoon SH, Shim YS, Park YH, et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells 2007; 25:2066–2073.

28. Chernykh ER, Stupak VV, Muradov GM, et al. Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull. Exp. Biol. Med. 2007; 143:543–547.

29. Kumar A, Kumar S, Narayanan R, Arul K, Baskaran M. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: A phase I/II clinical safety and primary efficacy data. Exp. Clin. Transplant. 2009; 7:241– 248.

30. Callera F, do Nascimento RX. Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: A preliminary safety study. Exp. Hematol. 2006; 34:130–13.

31. Cristante AF, Barros-Filho TE, Tatsui N, et al. Stem cells in the treatment of chronic spinal cord injury: Evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord 2009; 47:733–738.

32. Deda H, Inci MC, Kürekçi AE, et al. Treatment of chronic spinal cord injured patients with autologous bone marrowderived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy 2008; 10:565–574.

33. Rao YJ, Zhu WX, Du ZQ, et al. Effectiveness of olfactory ensheathing cell transplantation for treatment of spinal cord injury. Genet Mol Res. 2014; 13(2):4124-9.

34. García-Alias G, Lopez-Vales R, Fores J, Navarro X, Verdu E. Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat. J. Neurosci. Res. 2004; 75:632–641.

35. Kubasak MD, Jindrich DL, Zhong H, et al. OEG implantation and step training enhance hindlimb-stepping ability in adult spinal transected rats. Brain 2008; 131:264–276.

36. Munoz-Quiles C, Santos-Benito FF, Llamusí MB, Ramon-Cueto A. Chronic spinal injury repair by olfactory bulb ensheathing glia and feasibility for autologous therapy. J. Neuropathol. Exp. Neurol. 2009; 68:1294–1308.

37. Radtke C, Sasaki M, Lankford KL, Vogt PM, Kocsis JD. Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury. J. Rehabil. Res. Dev. 2008; 45:141–151.

38. Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 2000; 25:425–435.

39. Woodhall E, West AK, Chuah MI. Cultured olfactory ensheathing cells express nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor and their receptors. Brain Res Mol Brain Res. 2001; 88(1-2):203-13.

40. Mayeur A, Duclos C, Honoré A, et al. Potential of olfactory ensheathing cells from different sources for spinal cord repair. PLoS One 2013; 8(4):e62860.

41. Feron F, Perry C, Cochrane J, et al. Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain 2005; 128:2951–2960.

42. Mackay-Sim A, Feron F, Cochrane J, et al. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 2008; 131:2376–2386.

43. Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C, Peduzzi JD. Olfactory mucosa autografts in human spinal cord injury: A pilot clinical study. J. Spinal Cord Med 2006; 29:191–203.

44. Tabakow P, Jarmundowicz W, Czapiga B, et al. Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transplant. 2013; 22(9):1591-612.

45. Zheng Z, Liu G, Chen Y, Wei S. Olfactory ensheathing cell transplantation improves sympathetic skin responses in chronic spinal cord injury. Neural Regen Res. 2013; 8(30):2849-55.

46. Hsu YC, Lee DC, Chiu IM. Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant. 2007; 16:133–150.

47. Moreno-Manzano V, Rodríguez-Jiménez, FJ, García-Roselló M, et al. Activated spinal cord ependymal stem cells rescue neurological function. Stem Cells 2009; 27:733–743.

48. Barnabe´-Heider F, Frisen J. Stem cells for spinal cord repair. Cell Stem Cell 2008; 3:16–24.

49. 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.

50. Iwanami A, Kaneko S, Nakamura M, et al. Transplantation of human neural stem cells for spinal cord injury in primates. J. Neurosci. Res. 2005; 80:182–190.

51. Parr A. M, Kulbatski I, Zahir T, et al. (2008). Transplanted adult spinal cordderived neural stem/progenitor cells promote early functional recovery after rat spinal cord injury. Neuroscience 155:760–770.

Serbian Journal of Experimental and Clinical Research

The Journal of Faculty of Medical Sciences, University of Kragujevac

Journal Information

CiteScore 2018: 0.13

SCImago Journal Rank (SJR) 2018: 0.118
Source Normalized Impact per Paper (SNIP) 2018: 0.079


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 252 137 9
PDF Downloads 95 62 4