The Use of Mesenchymal Stem Cells in the Experimental and Clinical Therapy of Spinal Cord Injury


Authors: A. Hejčl 1,2;  P. Jendelová 2,3;  M. Sameš 1;  E. Syková 2,3
Authors‘ workplace: Neurochirurgická klinika UJEP a Krajská zdravotní a. s., Masarykova nemocnice v Ústí nad Labem, o. z. 1;  Ústav experimentální medicíny AV ČR, v. v. i., Praha 2;  Ústav neurověd, 2. LF UK v Praze 3
Published in: Cesk Slov Neurol N 2014; 77/110(5): 560-567
Category: Review Article

Podpořeno Grantovou agenturou České republiky 13- 00939S, 14- 14961S, grantem Lidské zdroje pro neurovědní výzkum v Královéhradeckém a Ústeckém kraji CZ.1.07/ 2.3.00/ 20.0274 a dále finančně podpořeno projektem LO1309 MŠMT ČR v rámci programu NPU I.

Overview

The use of mesenchymal stem cells (MSC) represents an experimental therapeutic modality in the treatment of spinal cord injury. MSC can be harvested from the bone marrow, fat tissue and other peripheral tissues from adult individuals. Compared to other types of stem cells, MSC are easy to access and expand and they can be used in autologous settings. Over the last 15 years, MSC have been widely studied in experimental spinal cord injury, especially in rodents, with promising results. MSC support remyelination of demyelinated axons, axonal sprouting, angiogenesis, have immunosuppressive effect and secrete neurotrophic factors that may led to functional improvement. These promising results led to launching of clinical studies in patients with spinal cord injury. Phase I/II clinical studies showed that the use of MSC represent a safe method. However, functional effect needs to be proved in further clinical studies. Data suggest that MSC will need to be combined with other methods, such as lesion bridging, scar tissue breakdown and blocking of inhibitory molecules. This paper provides an overview of the use of MSC in experimental and clinical SCI.

Key words:
spinal cord injury –  mesenchymal stem cells –  stem cell therapy –  clinical studies

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for bio­­medical papers.


Sources

1. Beneš V. Poranění míchy. Praha: Avicenum 1987.

2. Li J, Lepski G. Cell transplantation for spinal cord injury: a systematic review. Biomed Res Int 2013: 786475. doi: 10.1155/ 2013/ 786475.

3. Sykova E, Homola A, Mazanec R, Lachmann H, Konradova SL, Kobylka P et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 2006; 15(8– 9): 675– 687.

4. Samson D, Chanarin I, Reid CD. Recent advances in haematology. Postgrad Med J 1981; 57(665): 139– 149.

5. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143– 147.

6. Dominici M, Le Blanc K, Mueller I, Slaper‑ Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315– 317.

7. Krasulová E TM, Kozák T, Havrdová E. Autologous Hematopoietic Stem Cells Transplantation and its Cur­rent Role in Multiple Sclerosis Treatment. Cesk Slov Neurol N 2009; 72/ 105(3): 227– 234.

8. Kocsis JD, Honmou O. Bone marrow stem cells in experimental stroke. Prog Brain Res 2012; 201: 79– 98. doi: 10.1016/ B978‑ 0‑ 444‑ 59544‑ 7.00005‑ 6.

9. Soler B, Fadic R, von Bernhardi R. Stem cells therapy in amyotrophic lateral sclerosis treatment. A critical view. Rev Neurol 2011; 52(7): 426– 434.

10. Glavaski‑ Joksimovic A, Bohn MC. Mesenchymal stem cells and neuroregeneration in Parkinson‘s dis­ease. Exp Neurol 2013; 247: 25– 38. doi: 10.1016/ j.expneurol.2013.03.016.

11. Forostyak S, Jendelova P, Sykova E. The role of mesenchymal stromal cells in spinal cord injury, regenerative medicine and possible clinical applications. Biochimie 2013; 95(12): 2257– 2270. doi: 10.1016/ j.bio­chi.2013.08.004.

12. Sykova E, Jendelova P, Urdzikova L, Lesny P, Hejcl A.Bone marrow stem cells and polymer hydrogels –  two strategies for spinal cord injury repair. Cell Mol Neurobio­l 2006; 26(7– 8): 1113– 1129.

13. Urdzikova L, Jendelova P, Glogarova K, Burian M, Hajek M, Sykova E. Transplantation of bone marrow stem cells as well as mobilization by granulocyte‑ colony stimulating factor promotes recovery after spinal cord injury in rats. J Neurotrauma 2006; 23(9): 1379– 1391.

14. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 2002; 59(4): 514– 523.

15. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276(5309): 71– 74.

16. Li N, Sarojini H, An J, Wang E. Prosaposin in the secretome of marrow stroma‑ derived neural progenitor cells protects neural cells from apoptotic death. J Neurochem 2010; 112(6): 1527– 1538. doi: 10.1111/ j.1471‑ 4159.2009.06565.x.

17. Hao P, Liang Z, Piao H, Ji X, Wang Y, Liu Y et al. Conditioned medium of human adipose‑derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP‑ 43 expression. Metab Brain Dis 2014; 29(1): 193– 205. doi: 10.1007/ s11011‑ 014‑ 9490‑ y.

18. Koda M, Nishio Y, Kamada T, Someya Y, Okawa A,Mori C et al. Granulocyte colony‑ stimulating factor (G‑CSF) mobilizes bone marrow‑ derived cells into injured spinal cord and promotes functional recovery after compression‑induced spinal cord injury in mice. Brain Res 2007; 1149: 223– 231.

19. Hejcl A, Sedy J, Kapcalova M, Toro DA, Amemori T,Lesny P et al. HPMA‑ RGD hydrogels seeded with mesenchymal stem cells improve functional outcome in chronic spinal cord injury. Stem Cells Dev 2010; 19(10): 1535– 1546. doi: 10.1089/ scd.2009.0378.

20. Amemori T, Jendelova P, Ruzickova K, Arboleda D, Sykova E. Co‑ transplantation of olfactory ensheathing glia and mesenchymal stromal cells does not have synergistic effects after spinal cord injury in the rat. Cytotherapy 2010; 12(2) :212– 225. doi: 10.3109/ 14653240903440103.

21. Shin DA, Pennant WA, Yoon do H, Ha Y, Kim KN.Co‑ transplantation of bone marrow‑ derived mesenchymal stem cells and nanospheres containing FGF‑ 2 improve cell survival and neurological function in the injured rat spinal cord. Acta Neurochir (Wien) 2014; 156(2): 297– 303. doi: 10.1007/ s00701‑ 013‑ 1963‑ y.

22. Sasaki M, Honmou O, Akiyama Y, Uede T, Hashi K,Kocsis JD. Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia 2001; 35(1): 26– 34.

23. Akiyama Y, Radtke C, Kocsis JD. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 2002; 22(15): 6623– 6630.

24. 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(1): 17– 31.

25. 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(4): 2199– 2204.

26. 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(2): 278– 296.

27. Busch SA, Hamilton JA, Horn KP, Cuascut FX, Cutrone R, Lehman N et al. Multipotent adult progenitor cells prevent macrophage‑ mediated axonal dieback and promote regrowth after spinal cord injury. J Neurosci 2011; 31(3): 944– 953. doi: 10.1523/ JNEUROSCI.3566‑ 10.2011.

28. Schwartz M. „Tissue‑ repairing“ blood‑ derived macrophages are essential for healing of the injured spinal cord: from skin‑activated macrophages to infiltrating blood‑ derived cells? Brain Behav Immun 2010; 24(7): 1054– 1057. doi: 10.1016/ j.bbi.2010.01.010.

29. Zhukareva V, Obrocka M, Houle JD, Fischer I, Neuhuber B. Secretion profile of human bone marrow stromal cells: donor variability and response to inflammatory stimuli. Cytokine 2010; 50(3): 317– 321. doi: 10.1016/ j.cyto.2010.01.004.

30. Coumans JV, Lin TT, Dai HN, MacArthur L, McAtee M, Nash C et al. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci 2001; 21(23): 9334– 9344.

31. Hejcl A, Urdzikova L, Sedy J, Lesny P, Pradny M,Michalek J et al. Acute and delayed implantation of positively charged 2- hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat. J Neurosurg Spine 2008; 8(1): 67– 73. doi: 10.3171/ SPI‑ 08/ 01/ 067.

32. Zurita M, Vaquero J. Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation. Neuroreport 2004; 15(7): 1105– 1108.

33. Vaquero J, Zurita M, Oya S, Santos M. Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration? Neurosci Lett 2006; 398(1– 2): 129– 134.

34. Kim JW, Ha KY, Molon JN, Kim YH. Bone marrow‑ derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine (Phila Pa 1976) 2013; 38(17): E1065–E 1074. doi: 10.1097/ BRS.0b013e31829839fa.

35. Tom VJ, Sandrow‑ Feinberg HR, Miller K, Santi L,Connors T, Lemay MA et al. Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. J Neurosci 2009; 29(47): 14881– 14890. doi: 10.1523/ JNEUROSCI.3641‑ 09.2009.

36. Hejcl A, Ruzicka J, Kapcalova M, Turnovcova K, Krumbholcova E, Pradny M et al. Adjusting the chemical and physical properties of hydrogels leads to improved stem cell survival and tissue ingrowth in spinal cord injury reconstruction: a comparative study of four methacrylate hydrogels. Stem Cells Dev 2013; 22(20): 2794– 2805. doi: 10.1089/ scd.2012.0616.

37. Vanicky I, Urdzikova L, Saganova K, Cizkova D, Galik J. A simple and reproducible model of spinal cord injury induced by epidural balloon inflation in the rat. J Neurotrauma 2001; 18(12): 1399– 1407.

38. Cizkova D, Novotna I, Slovinska L, Vanicky I, Jergova S, Rosocha J et al. Repetitive intrathecal catheter delivery of bone marrow mesenchymal stromal cells improves functional recovery in a rat model of contusive spinal cord injury. J Neurotrauma 2011; 28(9): 1951– 1961. doi: 10.1089/ neu.2010.1413.

39. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO 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(8): 2066– 2073.

40. 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(2): 266– 278.

41. Saito F, Nakatani T, Iwase M, Maeda Y, Murao Y,Suzuki Y et al. Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. Restor Neurol Neurosci 2012; 30(2): 127– 136. doi: 10.3233/ RNN‑ 2011‑ 0629.

42. Quertainmont R, Cantinieaux D, Botman O, Sid S, Schoenen J, Franzen R. Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro‑angiogenic actions. PloS One 2012; 7(6): e39500. doi: 10.1371/ journal.pone.0039500.

43. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008; 15(10): 730– 738. doi: 10.1038/ gt.2008.39.

44. Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, Hamada H et al. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res 2010; 1343: 226– 235. doi: 10.1016/ j.brainres.2010.05.011.

45. Zhang D, He X. A meta‑analysis of the motion function through the therapy of spinal cord injury with intravenous transplantation of bone marrow mesenchymal stem cells in rats. PloS One 2014; 9(4): e93487. doi: 10.1371/ journal.pone.0093487.

46. Kishk NA, Gabr H, Hamdy S, Afifi L, Abokresha N, Mahmoud H et al. Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair 2010; 24(8): 702– 708. doi: 10.1177/ 1545968310369801.

47. Liu J, Han D, Wang Z, Xue M, Zhu L, Yan H et al. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy 2013; 15(2): 185– 191. doi: 10.1016/ j.jcyt.2012.09.005.

48. Jendelova P, Herynek V, DeCroos J, Glogarova K, Andersson B, Hajek M et al. Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles. Magn Reson Med 2003; 50(4): 767– 776.

49. Paul C, Samdani AF, Betz RR, Fischer I, Neuhuber B. Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976) 2009; 34(4): 328– 334. doi: 10.1097/ BRS.0b013e31819403ce.

50. Nishida H, Nakayama M, Tanaka H, Kitamura M, Hatoya S, Sugiura K et al. Evaluation of transplantation of autologous bone marrow stromal cells into the cerebrospinal fluid for treatment of chronic spinal cord injury in dogs. Am J Vet Res 2011; 72(8): 1118– 1123. doi: 10.2460/ ajvr.72.8.1118.

51. Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS et al. Schwann cell‑like remyelination following transplantation of human umbilical cord blood (hUCB)– derived mesenchymal stem cells in dogs with acute spinal cord injury. J Neurol Sci 2011; 300(1– 2): 86– 96. doi: 10.1016/ j.jns.2010.09.025.

52. Deng YB, Liu XG, Liu ZG, Liu XL, Liu Y, Zhou GQ. Implantation of BM mesenchymal stem cells into injured spinal cord elicits de novo neurogenesis and functional recovery: evidence from a study in rhesus monkeys. Cytotherapy 2006; 8(3): 210– 214.

53. Deng YB, Yuan QT, Liu XG, Liu XL, Liu Y, Liu ZG et al. Functional recovery after rhesus monkey spinal cord injury by transplantation of bone marrow mesenchymal‑ stem cell‑ derived neurons. Chin Med J 2005; 118(18): 1533– 1541.

54. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BHet al. Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte‑ macrophage colony stimulating factor. Tissue Eng 2005; 11(5– 6): 913– 922.

55. Park JH, Kim DY, Sung IY, Choi GH, Jeon MH, Kim KK et al. Long‑term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery 2012; 70(5): 1238– 1247. doi: 10.1227/ NEU.0b013e31824387f9.

56. Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord‑ injured mice. Proc Natl Acad Sci U S A 2005; 102(39): 14069– 14074.

57. 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– 178. doi: 10.1002/ stem.570.

58. Hejcl A, Lesny P, Pradny M, Michalek J, Jendelova P, Stulik J et al. Biocompatible hydrogels in spinal cord injury repair. Physiol Res 2008; 57 (Suppl 3): S121– S132.

59. Kubinova S, Horak D, Hejcl A, Plichta Z, Kotek J,Proks V et al. SIKVAV‑ modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. J Tissue Eng Regen Med 2013. doi: 10.1002/ term.1694. 

60. Hejcl A, Lesny P, Pradny M, Sedy J, Zamecnik J, Jendelova P et al. Macroporous hydrogels based on 2- hydroxyethyl methacrylate. Part 6: 3D hydrogels with positive and negative surface charges and polyelectrolyte complexes in spinal cord injury repair. J Mater Sci Mater Med 2009; 20(7): 1571– 1577. doi: 10.1007/ s10856‑ 009‑ 3714‑ 4.

61. Amr SM, Gouda A, Koptan WT, Galal AA, Abdel‑ Fattah DS, Rashed LA et al. Bridging defects in chronic spinal cord injury using peripheral nerve grafts combined with a chitosan‑ laminin scaffold and enhancing regeneration through them by co‑ transplantation with bone‑ marrow‑ derived mesenchymal stem cells: case series of 14 patients. J Spinal Cord Med 2014; 37(1): 54– 71. doi: 10.1179/ 2045772312Y.0000000069.

62. 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(2): 130–131.

63. Deda H, Inci MC, Kürekçi AE, Kayihan K, Ozgün E,Ustünsoy GE et al. Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy 2008; 10(6): 565–574. doi: 10.1080/14653240802241797.

64. Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant 2008; 17(12): 1277–1293.

65. Pal R, Venkataramana NK, Bansal A, Balaraju S,Jan M, Chandra R et al. Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy 2009; 11(7): 897–911. doi: 10.3109/14653240903253857.

66. Hammadi AA, Marino A, Farhan S. Clinical response of 277 patients with spinal cord injury to stem cell therapy in Iraq. Int J Stem Cells 2012; 5(1): 76–78.

67. Karamouzian S, Nematollahi-Mahani SN, Nakhaee N, Eskandary H. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg 2012; 114(7): 935–939.

68. Jiang PC, Xiong WP, Wang G, Ma C, Yao WQ, Kendell SF et al. A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury. Exp Ther Med 2013; 6(1): 140–146.

Labels
Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 5

2014 Issue 5

Most read in this issue
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account