Comparison of human adipose-derived stem cells and chondroitinase ABC transplantation on locomotor recovery in the contusion model of spinal cord injury in rats

Document Type : Original Article


1 Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, IranDepartment of Medical Basic Sciences, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, IranDepartment of Physiology, Tehran, Iran

4 Systems and Synthetic Biology Group, Bioeconomy Company, Tehran, Iran

5 Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, IranCellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

6 Department of Hematology, School of Allied Medical, Tehran University of Medical Sciences, Tehran, Iran

7 Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Sciences, Tehran, Iran


Objective(s):Spinal cord injury (SCI) is one of the most serious clinical diseases and its treatment has been a subject of interest to researchers. There are two important therapeutic strategies in the treatment of SCI: replacing lost tissue cells through cells implantation and scar elimination. Therefore, in this study we used human adipose-derived stem cells (hADSCs) implantation and injection of Chondroitinase ABC.
Aim of present study was to answer to this question: which one is more efficient for Improvement of locomotor recovery after SCI in rat? Transplantation of hADSCs or injection of ChABC.
Materials and Methods: The spinal cord of rats was injured by contusion using a weight-drop at the level of T8-9, the hADSCs and Chondroitinase ABC were infused in to the spinal cord tissue after injury. BBB test was performed and recorded for each animal weekly for 8 weeks. After the 8th weeks, Serial cross-sections were stained with cresyl violet and examined under a light microscope and area of cavity in the spinal cord was measured.
Results: At 8th weeks after injection, hADSCs and ChABC significantly promote locomotor function (P<0.01) and spinal cords of hADSCs and ChABC group had cavities much smaller than those of the control group (P<0.001).
Conclusion: Results of the present study shows dealing with inappropriate neuro-inhibitory environment and glial scar by ChABC have equal role compare to cell therapy (with hADSCs) for improving motor function after SCI and this result in adoption of proper therapeutic strategies for SCI intervention is important.


1. Pearse DD, Sanchez AR, Pereira FC, Andrade CM, Puzis R, Pressman Y, et al. Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery. Glia 2007; 55:976-1000.
2. Hulsebosch CE. Recent advances in pathophysi-ology and treatment of spinal cord injury. Adv Physiol Educ 2002; 26:238-255.
3. Dietz V, Curt A. Neurological aspects of spinal-cord repair: promises and challenges. Lancet neurol 2006; 5:688-694.
4. Kurnellas MP, Nicot A, Shull GE, Elkabes S. Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury. FASEB J 2005; 19:298-300. 
5. McDonald JW, Belegu V. Demyelination and remyelination after spinal cord injury. J Neurotrauma 2006; 23:345-359.
6. Von Euler M, Seiger A, Sundstrom E. Clip compression injury in the spinal cord: a correlative study of neurological and morphological alterations. Exp Neurol 1997; 145:502-510.
7. Pan JZ, Ni L, Sodhi A, Aguanno A, Young W, Hart RP. Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion. J Neurosci Res 2002; 68:315-322.
8. Jung K, Min DS, Sim KB, Ahn M, Kim H, Cheong J,              et al. Upregulation of phospholipase D1 in the spinal cords of rats with clip compression injury. Neurosci Lett 2003; 336:126-130.
9. Myckatyn TM, Mackinnon SE, McDonald JW. Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury. Transpl Immunol 2004; 12:343-358.
10. Himes BT, Neuhuber B, Coleman C, Kushner R, Swanger SA, Kopen GC, et al. Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair 2006; 20:278-296.
11. Cummings BJ, Uchida N, Tamaki SJ, Anderson AJ. Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function. Neurol Res 2006; 28:474-481.
12. Kalbermatten DF, Schaakxs D, Kingham PJ, Wiberg M. Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat. Cell Tissue Res 2011; 344:251-260. 
13. Dyer JK, Bourque JA, Steeves JD. The role of complement in immunological demyelination of the mammalian spinal cord. Spinal cord 2005; 43:417-425.
14. Harel NY, Strittmatter SM. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci 2006; 7:603-616.
15. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci 2004; 5:146-156.
16. Sandvig A, Berry M, Barrett LB, Butt A, Logan A. Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. Glia 2004; 46:225-251.
17. Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition. J Neurosci 2003; 23:9276-9288.
18. Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002; 4164:636-640.
19. Barritt AW, Davies M, Marchand F, Hartley R, Grist J, Yip P, et al. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci 2006; 26:10856-10867.
20. Ramer LM, Ramer MS, Steeves JD. Setting the stage for functional repair of spinal cord injuries: a cast of thousands. Spinal cord 2005; 43:134-161.
21. Dubois SG, Floyd EZ, Zvonic S, Kilroy G, Wu X, Carling S, et al. Isolation of human adipose-derived stem cells from biopsies and liposuction specimens. Methods Mol Biol 2008; 449:69-79. 
22. Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 1995; 12:1-21.
23. Kundi S, Bicknell R, Ahmed Z. Spinal Cord Injury: current Mammalian Models. Am J Neurosci 2013;4:1-12.
24. Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 2002; 99:2199-2204.
25. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 1999; 19:8182-8198.
26. Zhang Z, Krebs CJ, Guth L. Experimental analysis of progressive necrosis after spinal cord trauma in the rat: etiological role of the inflammatory response. Exp Neurol 1997; 143:141-152.
27. Michele Basso D, Murray M, Goldberger ME. Differential recovery of bipedal and overground locomotion following complete spinal cord hemisection in cats. Restor Neurol Neurosci 1994; 7:95-110. 
28. Edgerton VR, Roy RR, Hodgson JA, Prober RJ, de Guzman CP, de Leon R. Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input. J Neurotrauma 1992; 9:S119-128.
29. Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in the adult cat. Brain Res 1987; 412:84-95.
30. Ankeny DP, McTigue DM, Jakeman LB. Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats. Exp Neurol 2004; 190:17-31.
31. Lee TH. Transplantation of human adipose-derived stromal cells promotes functional recovery of rat spinal cord injury. Korean J Anat 2005; 38:461-468.
32. Wu S, Suzuki Y, Ejiri Y, Noda T, Bai H, Kitada M,           et al. Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res 2003; 72:343-351.
33. Chopp M, Zhang XH, Li Y, Wang L, Chen J, Lu D,           et al. Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 2000; 11:3001-3005.
34. Horner PJ, Power AE, Kempermann G, Kuhn HG, Palmer TD, Winkler J, et al. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J Neurosci 2000; 20: 2218-2228.
35. Chow SY, Moul J, Tobias CA, Himes BT, Liu Y, Obrocka M, et al. Characterization and intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embryonic rat spinal cord. Brain Res 2000; 874:87-106.
36. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998; 176:57-66.
37. Eaves CJ, Cashman JD, Kay RJ, Dougherty GJ, Otsuka T, Gaboury LAet al. Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in longterm human marrow cultures. Analysis of positive and negative regulators produced by stromal cells within the adherent layer. Blood 1991;78:110-117.
38. Chen X, Katakowski M, Li Y, Lu D, Wang L, Zhang L, et al. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 2002; 69:687-691.
39. Ohta M, Suzuki Y, Noda T, Ejiri Y, Dezawa M, Kataoka K, et al. Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol 2004; 187:266-278.
40. 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.
41. Zhang C, He X, Li H, Wang G. Chondroitinase ABC plus bone marrow mesenchymal stem cells for repair of spinal cord injury. Neural Regen Res 2013; 8:965-974.