The effect of neurotransplantation of various allogeneic tissue types to motor function restore after experimental spinal cord injury


  • Volodymyr V. Medvediev Bogomolets National Medical University, Kyiv, Ukraine



spinal cord injury, tissue neurotransplantation, motor function recovery, pathophysiology, tissue neuroengineering


Objective. To examine the effect of different tissue type of neurotransplantation on the locomotor function restoration after experimental spinal cord injury.

Materials and methods. Animals: inbred albino male rats (5.5 months, 300 g); experimental groups: 1 — spinal cord injury + immediate homotopical transplantation of olfactory bulb tissue (TOBT, n=34), 2 — spinal cord injury + analogous transplantation of fetal (E18) cerebellum tissue (TFСT, n=15), 3 — spinal cord injury + analogous transplantation of fetal (E18) kidney tissue (TFKT, n=8), 4 — spinal cord injury only in similar (control–1, n=16) and different (control–2, n=40) experimental seasons. Model of injury — left-side spinal cord hemisection at ТXI level; monitoring the ipsilateral hindlimb function indicator (IHL FI) — the Вasso–Вeattie–Вresnahan scale (BBB).

Results. The predominance (p> 0.05) of the IHL FI after approved types of neurotransplantation has been noted when comparing with the control group–1 — at the 1st–5th week (ТОBT), 1st–2nd and 6th–7th week (TFСT), and at the end of the 8th week (TFKT); when comparing with the control group–2 — at the 1st–3rd (ТОBT) and 1st (TFСT) week of the experiment. The maximum value of the IHL FI has been observed at the 2nd (ТОBT, 3,7±0,5 points ВВВ), 1st, 6th–7th (TFСT, 3,6±0,8 points ВВВ), 12th and 20th (TFKT, 3,6±1,2 points ВВВ) weeks, minimum value of the IHL FI — at the 24th (ТОBT, 2,4±0,6 points ВВВ), 3rd (TFСT, 3,0±0,9 points ВВВ) and 1st (TFKT, 1,9±1,1 points ВВВ) week of the experiment. Average IHL FI values of the three experimental groups at the 24th week of the experiment have been amounted to 2,4–3,3 points BBB and comprised in a range of control groups final mean values (1,6–3,4 балла ВВВ). Significant differences between the IHL FI values of the groups ТОBT, TFСT and TFKT have not been observed during the experiment. In the case of TOBT significant changes of IHL FI have been noted during the 2nd (increase), 6th–7th and 16th–24th week (reduced to a level below the 1st week); in the case of TFKT — at the 1st–3rd week (increase); in the case of TFСT no significant changes have been identified. A common feature of the dynamics of the three experimental groups is prevalence of IHL FI values over the control during the first few weeks and lack of progression during further period of observation, that can be interpreted in a view of angiogenic, neurotropic, proinflammatory and mediator effects of the grafts.

Conclusion. Approved types of neurotransplantation provide a temporary effect, continuing during the first month of the traumatic process; the study of the pathophysiological mechanisms of this effect can significantly improve understanding of tissue processes after multicomponent neuroengineering interventions.

Author Biography

Volodymyr V. Medvediev, Bogomolets National Medical University, Kyiv

Department of Neurosurgery


1. Filler A. A historical hypothesis of the first recorded neurosurgical operation: Isis, Osiris, Thoth, and the origin of the djed cross. Neurosurg. Focus. 2007;23(1):E6. [CrossRef] [PubMed]

2. Eli [Electron resource]. Orthodox Encyclopedia [Kirill, Patriarch. Moscow and All Russia, ed.]. Moscow: Publishing house of the Moscow Patriarchate; 1998–2014. Russian, Available at:

3. Biblia: Knygy Svyaschennogo Pysannya Starogo ta Novogo Zavitu [Bible: Book of the Scriptures of the Old and New Testament]. Kyiv: Publishing house of the Kiev Patriarchate Ukrainian Orthodox Church; 2004. Ukrainian.

4. van Middendorp JJ, Sanchez GM, Burridge AL. The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries. Eur Spine J. 2010;19(11):1815-23, [CrossRef]

5. Ghaffari F, Naseri M, Movahhed M, Zargaran A. Spinal traumas and their treatments according to Avicenna’s Canon of Medicine. World Neurosurg. 2015;84(1):173-7, [CrossRef] [PubMed]

6. Khvedchenya SB. Ilya Muromets — sviatoj bogatyr [Ilya Muromets — a holy warrior]. Kiev: Geografika; 2005. Russian.

7. Tsymbaliuk VI, Medvediev VV. Nejrogennye stvolovye kletky [Neural stem cells]. Kiev: Koval’; 2005. Russian.

8. Dцbrцssy M, Busse M, Piroth T, Rosser A, Dunnett S, Nikkhah G. Neurorehabilitation with neural transplantation. Neurorehabil. Neural Repair. 2010;24(8):692-701, [CrossRef] [PubMed]

9. Myers SA, Bankston AN, Burke DA, Ohri SS, Whittemore SR. Does the preclinical evidence for functional remyelination following engraftment into the injured spinal cord support progression to clinical trials? Exp Neurol. 2016;283(pt.B):560-72. [CrossRef] [PubMed]

10. Dobkin BH. Recommendations for publishing case studies of cell transplantation for spinal cord injury. Neurorehabil. Neural Repair. 2010;24(8):687-91, [CrossRef] [PubMed]

11. Assunзгo-Silva RC, Gomes ED, Sousa N, Silva NA, Salgado AJ. Hydrogels and cell based therapies in spinal cord injury regeneration. Stem Cells International. 2015;2015:1-24. [CrossRef] [PubMed]

12. Siebert JR, Eade AM, Osterhout DJ. Biomaterial approaches to enhancing neurorestoration after spinal cord injury: strategies for overcoming inherent biological obstacles. BioMed Res. Int. 2015;2015:1-20. [CrossRef] [PubMed]

13. Tsintou M, Dalamagkas K, Seifalian AM. Advances in regenerative therapies for spinal cord injury: a biomaterials approach. Neural Regen. Res. 2015;10(5):726-42, [CrossRef] [PubMed]

14. Volpato FZ, Fьhrmann T, Migliaresi C, Hutmacher DW, Daltonet PD. Using extracellular matrix for regenerative medicine in the spinal cord. Biomaterials. 2013;34(21):4945-55. [CrossRef] [PubMed]

15. Steeves JD. Bench to bedside: challenges of clinical translation. Prog. Brain Res. 2015;218:227-39. [CrossRef] [PubMed]

16. Chang JC, Leung M, Gokozan HN. Gygli PE, Catacutan FP, Czeisler C, Otero JJ. Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice. J Neuropatol Exp Neurol. 2015;74(3):261-72. [CrossRef] [PubMed]

17. Marzban H., Del Bigio MR, Alizadeh J, Ghavami S, Zachariah RM, Rastegar M. Cellular commitment in the developing cerebellum. Fron. Cel. Neurosci. 2015;8:1-26. [CrossRef] [PubMed]

18. Ma M, Wu W, Li Q, Li J, Sheng Z, Shi J, Zhang M, Yang H, Wang Z, Sun R, Fei J. N-myc is a key switch regulating the proliferation cycle of postnatal cerebellar granule cell progenitors. Sci Rep 2015;5:1-13. [CrossRef] [PubMed]

19. Leffler SR, Leguй E, Aristizбbal O, Joyner AL, Peskin CS, Turnbull DH. A mathematical model of granule cell generation during mouse cerebellum development. Bull Math Biol. 2016;78(5):859-78, [CrossRef] [PubMed]

20. Hoshino M. Neuronal subtype specification in the cerebellum and dorsal hindbrain. Dev Growth Differ. 2012;54(3):317-26. [CrossRef] [PubMed]

21. Sentilhes L, Michel C, Lecourtois M, Catteau J, Bourgeois P, Laudenbach V, Marret S, Laquerriere A. Vascular endothelial growth factor and its high–affinity receptor (VEGFR–2) are highly expressed in the human forebrain and cerebellum during development. J Neuropatho. Exp Neurol. 2010;69(2):111-28. [CrossRef] [PubMed]

22. Darland DC, Cain JT, Berosik MA, Cain JT, Berosik MA, Saint-Geniez M, Odens PW, Schaubhut GJ, Frisch S, Stemmer-Rachamimov A, Darland T, D’Amore PA. Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development. Dev Biol. 2011;358(1):9-22. [CrossRef] [PubMed]

23. Jankowski J, Miething A, Schilling K, Oberdick J, Baader S. Cell death as a regulator of cerebellar histogenesis and compartmentation. Cerebellum. 2011;10(3): 373-92. [CrossRef] [PubMed]

24. Kilpatrick DL, Wang W, Gronostajski R, Litwack ED. Nuclear factor I and cerebellar granule neuron development: an intrinsic-extrinsic interplay. Cerebellum. 2012;11(1):41-9. [CrossRef] [PubMed]

25. De Luca A, Cerrato V, Fuca E, Parmigiani E, Buffo A, Leto K. Sonic hedgehog patterning during cerebellar development. Cel. Mol Life Sci. 2016;73(2):291-303. [CrossRef] [PubMed]

26. Nagayama S, Homma R, Imamura F. Neuronal organization of olfactory bulb circuits. Front Neural Circuits. 2014;8:1-19. [CrossRef] [PubMed]

27. Imai Т. Construction of functional neuronal circuitry in the olfactory bulb. Semin Cell Develop Biol. 2014;35:180-8. [CrossRef] [PubMed]

28. Kosaka T, Kosaka K. Neuronal organization of the main olfactory bulb revisited. Anat Ssi Int. 2016;91(2):115-27. [CrossRef] [PubMed]

29. Lazarini F, Gabellec M-M, Moigneu C, de Chaumont F, Olivo-Marin JC, Lledo PM. Adult neurogenesis restores dopaminergic neuronal loss in the olfactory bulb. J Neurosci. 2014;34(43):14430-42. [CrossRef] [PubMed]

30. Tsymbaliuk VI, Medvediev VV., abo mozochok [Cerebellum]. Vinnytsa: Nova Knyga; 2010. Ukrainian.

31. Fanni D, Sanna A, Gerosa C, Puddu M, Faa G, Fanos V. Each niche has an actor: multiple stem cell niches in the preterm kidney. Ital J Pediatr. 2015;41:1-8. [CrossRef] [PubMed]

32. Halt KJ, Parssinen HE, Junttila SM, Saarela U, Sims-Lucas S, Koivunen P, Myllyharju J, Quaggin S, Skovorodkin IN, Vainio SJ. CD146+ cells are essential for kidney vasculature development. Kidney Int. 2016;90(2):311-24. [CrossRef] [PubMed]

33. Gnudi L, Benedetti S, Woolf AS, Long DA. Vascular growth factors play critical roles in kidney glomeruli. Clin Sc. (Lond). 2015;129(12):1225-36. [CrossRef] [PubMed]

34. Eremina V, Quaggina SE. The role of VEGF–A in glomerular development and function. Curr Ohin Nephrol Hypertens. 2004;13(1):9-15. [PubMed]

35. Reidy KJ, Rosenblum ND. Cell and molecular biology of kidney development. Semin Nephrol. 2009;29(4):321-37. [CrossRef] [PubMed]

36. Woolf AS, Gnudi L, Long DA. Roles of angiopoietins in kidney development and disease. J Am Soc Nephrol. 2009;20(2):239-44. [CrossRef] [PubMed]

37. Tsymbaliuk V, Medvediev V, Semenova V, Grydina N, Senchyk Yu, Velychko O, Dychko S, Vaslovych V. [The model of lateral spinal cord hemisection. Part I. The technical, pathomorphological, clinical and experimental peculiarities]. Ukrainian Neurosurgical Journal. 2016; (2):18–27. [Abstract/Full Text]

38. Tsymbaliuk VI, Medvediev VV. Spinnoj mozg. Elegia nadezhdy [Spinal cord. Elegy of hope]. Vinnitsa: Nova Knyga; 2010. Russian.

39. Ng MTL, Stammers AT, Kwon BK. Vascular disruption and the role of angiogenic proteins after spinal cord injury. Trans. Stroke Res. 2011;2(4):474-91. [CrossRef] [PubMed]

40. Casella GTB, Marcillo A, Bunge MB, Wood PM. New vascular tissue rapidly replaces neural parenchyma and vessels destroyed by a contusion injury to the rat spinal cord. Exp Neurol. 2002;173(1):63-76. [CrossRef] [PubMed]

41. Yu SW, Friedman B, Cheng Q, Lyden PD. Stroke-evoked angiogenesis results in a transient population of microvessels. J Cereb Blood Flow Metab. 2007;27(4):755-63. [CrossRef] [PubMed]

42. Chi OZ, Hunter C, Liu X, Weiss HR. Effects of anti-VEGF antibody on blood–brain barrier disruption in focal cerebral ischemia. Exp Neurol. 2007;204(1):283-87. [CrossRef] [PubMed]

43. Van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams S-P, van Lookeren Campagne M, Ferrara N. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest. 1999;104(11):1613-20. [CrossRef] [PubMed]

44. Tsymbaliuk VI, Luzan BM, Dmyterko IP, Marushchenko MO, Medvediev VV, Troyan OI. Neirokhirurgia: Pidruchnyk / Tsymbaliuk ed. [Neurosurgery: Handbook]. Vinnitsa: Nova Knyga; 2010. Ukrainian.

45. De Almodovar CR, Lambrechts D, Mazzone M, Carmeliet P. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009; 89(2):607-48. [CrossRef] [PubMed]

46. Ng Y-S, Rohan R, Sunday ME, Demello DE, D’Amore PA. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev. Dyn. 2001;220(2):112-21. [CrossRef] [PubMed]

47. Muhl L, Moessinger C, Adzemovic MZ, Dijkstra MH, Nilsson I, Zeitelhofer M, Hagberg CE, Huusko J, Falkevall A, Ylд-Herttuala S, Eriksson U. Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. Cel. Tissue Res. 2016;365(1):51-63. [CrossRef] [PubMed]

48. Hou Y, Shin Y-J, Han EJ, Choi J-S, Park J-M, Cha J-H, Choi J-Y, Lee M-Y. Distribution of vascular endothelial growth factor receptor–3/Flt4 mRNA in adult rat central nervous system. J Chem Neuroanat. 2011;42(1):56-64. [CrossRef] [PubMed]

49. Yamaya S, Ozawa H, Kanno H, Kishimoto KN, Sekiguchi A, Tateda S, Yahata K, Ito K, Shimokawa H, Itoi E. Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury. . Neurosurg. 2014;121(6):1514-25. [CrossRef] [PubMed]

50. Kamei N, Kwon S-M, Ishikawa M, Ii M, Nakanishi K, Yamada K, Hozumi K, Kawamoto A, Ochi M, Asahara T. Endothelial progenitor cells promote astrogliosis following spinal cord injury through Jagged1-dependent Notch signaling. J Neurotrauma. 2012;29(9):1758-69. [CrossRef] [PubMed]

51. Kamei N, Kwon S-M, Kawamoto A, Ii M, Ishikawa M, Ochi M, Asahara T. Contribution of bone marrow-derived endothelial progenitor cells to neovascularization and astrogliosis following spinal cord injury. J Neursci. Res. 2012;90(12):2281-92. [CrossRef] [PubMed]

52. Pajer K, Feichtinger G, Mбrton G, Sabitzer S, Klein D, Redl H, Nуgrбdi A. Cytokine signaling by grafted neuroectodermal stem cells rescues motoneurons destined to die. Exp Neurol. 2014;261:180-9. [CrossRef] [PubMed]

53. Pajer K, Nemes C, Berzsenyi S, Kovбcs KA, Pirity MK, Pajenda G, Nуgrбdi A, Dinnyйs A. Grafted murine induced pluripotent stem cells prevent death of injured rat motoneurons otherwise destined to die. Exp. Neurol. 2015;269:188-201. [CrossRef] [PubMed]

54. Praet J, Santermans E, Daans J, Le Blon D, Hoornaert C, Goossens H, Hens N, Van der Linden A, Berneman Z, Ponsaerts P. Early inflammatory responses following cell grafting in the CNS trigger activation of the subventricular zone: a proposed model of sequential cellular events. Cell Transplant. 2015;24(8):1481-92. [CrossRef] [PubMed]

55. Le Blon D, Hoornaert C, Detrez JR, Bevers S, Daans J, Goossens H, De Vos WH, Berneman Z, Ponsaerts P. Immune remodelling of stromal cell grafts in the central nervous system: therapeutic inflammation or (harmless) side-effect? J Tissue Eng Regen Med. 2016 [Epub ahead of print]. [CrossRef] [PubMed]

56. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nature Reviews. 2009;9(6):449-56. [CrossRef] [PubMed]

57. Kapadia M, Sakic B. Autoimmune and inflammatory mechanisms of CNS damage. Prog Neurobiol. 2011;95(3):301-33. [CrossRef] [PubMed]

58. Levite M. Glutamate receptor antibodies in neurological diseases: Anti-AMPA-GluR3 antibodies, Anti-NMDA-NR1 antibodies, Anti-NMDA-NR2A/B antibodies, Anti-mGluR1 antibodies or Anti-mGluR5 antibodies are present in subpopulations of patients with either: Epilepsy, Encephalitis, Cerebellar Ataxia, Systemic Lupus Erythematosus (SLE) and Neuropsychiatric SLE, Sjogren’s syndrome, Schizophrenia, Mania or Stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor’s expression, impair glutamate-induced signaling and function, activate Blood Brain Barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and Ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm. 2014;121(8):1029-75. [CrossRef] [PubMed]

59. Bakpa OD, Reuber M, Irani SR. Antibody-associated epilepsies: clinical features, evidence for immunotherapies and future research questions. Seizure. 2016;41:26-41. [CrossRef] [PubMed]

60. Heckman CJ, Enoka RM. Motor unit. Compr Physiol. 2012;2(4):2629-82. [CrossRef] [PubMed]

61. D’Amico JM, Condliffe EG, Martins KJB, Bennett DJ, Gorassini MA. Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity. Front Int Neurosci. 2014;8(Art.36):1-24. [CrossRef] [PubMed]

62. Ditunno JF, Little JW, Tessler A, Burns AS. Spinal shock revisited : a four-phase model. Spinal Cord. 2004;42(7):383-95. [CrossRef] [PubMed]

63. Wienecke J, Westerdahl A-C, Hultborn H, Kiehn O, Ryge J. Global gene expression analysis of rodent motor neurons following spinal cord injury associate molecular mechanisms with development of postinjury spasticity. J Neurophysiol. 2010;103(2):761-78. [CrossRef] [PubMed]

64. Wang Y-F, Parpura V. Central role of maladapted astrocytic plasticity in ischemic brain edema formation. Front Cell Neurosci. 2016;10(Art.129):1-8. [CrossRef] [PubMed]

65. Lee K-E, Cho K-O, Choi Y-S, Kim SY. The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia. Korean J. Physiol Pharmacol. 2016;20(2):185-92. [CrossRef] [PubMed]

66. Jeitner TM, Battaile K, Cooper AJL. Critical evaluation of the changes in glutamine synthetase activity in models of cerebral stroke. Neurochem Res. 2015;40(12):2544-56. [CrossRef] [PubMed]

67. Centonze D. Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways. Eur Neurol. 2014;72(suppl.1):6-8. [CrossRef] [PubMed]

68. Piltti K, Salazar DL, Uchida N, Cummings BJ, Anderson AJ. Safety of human neural stem cell transplantation in chronic spinal cord injury. Stem Cell Transl Med. 2013;2(12):961-74. [CrossRef] [PubMed]



How to Cite

Medvediev, V. V. (2017). The effect of neurotransplantation of various allogeneic tissue types to motor function restore after experimental spinal cord injury. Ukrainian Neurosurgical Journal, (1), 11–23.



Original articles