Journal of Korean Neurosurgical Society

  • 제63권2호
  • /
  • Pages.153-162
  • /
  • 2020
  • /
  • 2005-3711(pISSN)
  • /
  • 1598-7876(eISSN)
대한신경외과학회 (The Korean Neurosurgical Society)
권호 표지
DOI QR코드

DOI QR Code

Current Status and Future Strategies to Treat Spinal Cord Injury with Adult Stem Cells

  • Jeong, Seong Kyun (Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Il (Department of Neurological Surgery, Hallym University Dongtan Sacred Heart Hospital) ;
  • Jeon, Sang Ryong (Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine)
  • 투고 : 2019.06.23
  • 심사 : 2019.09.17
  • 발행 : 2020.03.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Spinal cord injury (SCI) is one of the most devastating conditions and many SCI patients suffer neurological sequelae. Stem cell therapies are expected to be beneficial for many patients with central nervous system injuries, including SCI. Adult stem cells (ASCs) are not associated with the risks which embryonic stem cells have such as malignant transformation, or ethical problems, and can be obtained relatively easily. Consequently, many researchers are currently studying the effects of ASCs in clinical trials. The environment of transplanted cells applied in the injured spinal cord differs between the phases of SCI; therefore, many researchers have investigated these phases to determine the optimal time window for stem cell therapy in animals. In addition, the results of clinical trials should be evaluated according to the phase in which stem cells are transplanted. In general, the subacute phase is considered to be optimal for stem cell transplantation. Among various candidates of transplantable ASCs, mesenchymal stem cells (MSCs) are most widely studied due to their clinical safety. MSCs are also less immunogenic than neural stem/progenitor cells and consequently immunosuppressants are rarely required. Attempts have been made to enhance the effects of stem cells using scaffolds, trophic factors, cytokines, and other drugs in animal and/or human clinical studies. Over the past decade, several clinical trials have suggested that transplantation of MSCs into the injured spinal cord elicits therapeutic effects on SCI and is safe; however, the clinical effects are limited at present. Therefore, new therapeutic agents, such as genetically enhanced stem cells which effectively secrete neurotrophic factors or cytokines, must be developed based on the safety of pure MSCs.

키워드

참고문헌

  1. Al-Zoubi A, Jafar E, Jamous M, Al-Twal F, Al-Bakheet S, Zalloum M, et al. : Transplantation of purified autologous leukapheresis-derived CD34+ and CD133+ stem cells for patients with chronic spinal cord injuries: long-term evaluation of safety and efficacy. Cell Transplant 23 Suppl 1 : S25-S34, 2014
  2. Anderson KD, Guest JD, Dietrich WD, Bartlett Bunge M, Curiel R, Dididze M, et al. : Safety of autologous human schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma 34 : 2950-2963, 2017 https://doi.org/10.1089/neu.2016.4895
  3. Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U : Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 45 : 4251-4255, 2004 https://doi.org/10.1167/iovs.03-1108
  4. Bhanot Y, Rao S, Ghosh D, Balaraju S, Radhika CR, Satish Kumar KV : Autologous mesenchymal stem cells in chronic spinal cord injury. Br J Neurosurg 25 : 516-522, 2011 https://doi.org/10.3109/02688697.2010.550658
  5. Bozkurt G, Mothe AJ, Zahir T, Kim H, Shoichet MS, Tator CH : Chitosan channels containing spinal cord-derived stem/progenitor cells for repair of subacute spinal cord injury in the rat. Neurosurgery 67 : 1733-1744, 2010 https://doi.org/10.1227/NEU.0b013e3181f9af35
  6. Chen BK, Madigan NN, Hakim JS, Dadsetan M, McMahon SS, Yaszemski MJ, et al. : GDNF Schwann cells in hydrogel scaffolds promote regional axon regeneration, remyelination and functional improvement after spinal cord transection in rats. J Tissue Eng Regen Med 12 : e398-e407, 2018 https://doi.org/10.1002/term.2431
  7. Christodoulou I, Goulielmaki M, Devetzi M, Panagiotidis M, Koliakos G, Zoumpourlis V : Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review. Stem Cell Res Ther 9 : 336, 2018 https://doi.org/10.1186/s13287-018-1078-8
  8. Deda H, Inci MC, Kurekci AE, Kayihan K, Ozgun E, Ustunsoy GE, et al. : Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year followup. Cytotherapy 10 : 565-574, 2008 https://doi.org/10.1080/14653240802241797
  9. di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, Kalbermatten DF : Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg 63 : 1544-1552, 2010 https://doi.org/10.1016/j.bjps.2009.09.012
  10. Ding DC, Chang YH, Shyu WC, Lin SZ : Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant 24 : 339-347, 2015 https://doi.org/10.3727/096368915X686841
  11. Dlouhy BJ, Awe O, Rao RC, Kirby PA, Hitchon PW : Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient: case report. J Neurosurg Spine 21 : 618-622, 2014 https://doi.org/10.3171/2014.5.SPINE13992
  12. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, et al. : Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45 : 190-205, 2007 https://doi.org/10.1038/sj.sc.3102007
  13. Gage FH : Mammalian neural stem cells. Science 287 : 1433-1438, 2000 https://doi.org/10.1126/science.287.5457.1433
  14. 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 17 : 1277-1293, 2008 https://doi.org/10.3727/096368908787648074
  15. Ghobrial GM, Anderson KD, Dididze M, Martinez-Barrizonte J, Sunn GH, Gant KL, et al. : Human neural stem cell transplantation in chronic cervical spinal cord injury: functional outcomes at 12 months in a phase II clinical trial. Neurosurgery 64 (CN_suppl_1) : 87-91, 2017 https://doi.org/10.1093/neuros/nyx242
  16. Gonzalez F, Boue S, Izpisua Belmonte JC : Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat Rev Genet 12 : 231-242, 2011 https://doi.org/10.1038/nrg2937
  17. 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 19 : 1535-1546, 2010 https://doi.org/10.1089/scd.2009.0378
  18. Hori J, Ng TF, Shatos M, Klassen H, Streilein JW, Young MJ : Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 21 : 405-416, 2003 https://doi.org/10.1634/stemcells.21-4-405
  19. Hur JW, Cho TH, Park DH, Lee JB, Park JY, Chung YG : Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: a human trial. J Spinal Cord Med 39 : 655-664, 2016 https://doi.org/10.1179/2045772315Y.0000000048
  20. Hwang NS, Varghese S, Elisseeff J : Controlled differentiation of stem cells. Adv Drug Deliv Rev 60 : 199-214, 2008 https://doi.org/10.1016/j.addr.2007.08.036
  21. Jeong JH, Lee JH, Jin ES, Min JK, Jeon SR, Choi KH : Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien) 152 : 1771-1777, 2010 https://doi.org/10.1007/s00701-010-0698-2
  22. Kanno H, Pearse DD, Ozawa H, Itoi E, Bunge MB : Schwann cell transplantation for spinal cord injury repair: its significant therapeutic potential and prospectus. Rev Neurosci 26 : 121-128, 2015 https://doi.org/10.1515/revneuro-2014-0068
  23. 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 Neuros 114 : 935-939, 2012 https://doi.org/10.1016/j.clineuro.2012.02.003
  24. Keilhoff G, Goihl A, Langnase K, Fansa H, Wolf G : Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur J Cell Biol 85 : 11-24, 2006 https://doi.org/10.1016/j.ejcb.2005.09.021
  25. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K : Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24 : 1294-1301, 2006 https://doi.org/10.1634/stemcells.2005-0342
  26. 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 24 : 702-708, 2010 https://doi.org/10.1177/1545968310369801
  27. Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer R, et al. : Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3 : 173-181, 2005 https://doi.org/10.3171/spi.2005.3.3.0173
  28. Lee HY, Hong IS : Double-edged sword of mesenchymal stem cells: cancer-promoting versus therapeutic potential. Cancer Sci 108 : 1939-1946, 2017 https://doi.org/10.1111/cas.13334
  29. 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 29 : 191-203; discussion 204-246, 2006 https://doi.org/10.1080/10790268.2006.11753874
  30. Lu P, Jones LL, Snyder EY, Tuszynski MH : Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181 : 115-129, 2003 https://doi.org/10.1016/S0014-4886(03)00037-2
  31. Luo L, Albashari AA, Wang X, Jin L, Zhang Y, Zheng L, et al. : Effects of transplanted heparin-poloxamer hydrogel combining dental pulp stem cells and bFGF on spinal cord injury repair. Stem Cells Int 2018 : 2398521, 2018
  32. Matsuse D, Kitada M, Kohama M, Nishikawa K, Makinoshima H, Wakao S, et al. : Human umbilical cord-derived mesenchymal stromal cells differentiate into functional Schwann cells that sustain peripheral nerve regeneration. J Neuropathol Exp Neurol 69 : 973-985, 2010 https://doi.org/10.1097/NEN.0b013e3181eff6dc
  33. McDonough A, Martinez-Cerdeno V : Endogenous proliferation after spinal cord injury in animal models. Stem Cells Int 2012 : 387513, 2012 https://doi.org/10.1155/2012/387513
  34. Mendonca MV, Larocca TF, de Freitas Souza BS, Villarreal CF, Silva LF, Matos AC, et al. : Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res Ther 5 : 126, 2014 https://doi.org/10.1186/scrt516
  35. Min J, Kim JH, Choi KH, Yoon HH, Jeon SR : Is there additive therapeutic effect when GCSF combined with adipose-derived stem cell in a rat model of acute spinal cord injury? J Korean Neurosurg Soc 60 : 404-416, 2017 https://doi.org/10.3340/jkns.2016.1010.008
  36. Mothe AJ, Tator CH : Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci 31 : 701-713, 2013 https://doi.org/10.1016/j.ijdevneu.2013.07.004
  37. Oh SK, Choi KH, Yoo JY, Kim DY, Kim SJ, Jeon SR : A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery 78 : 436-447; discussion 447, 2016 https://doi.org/10.1227/neu.0000000000001056
  38. Okada S, Ishii K, Yamane J, Iwanami A, Ikegami T, Katoh H, et al. : In vivo imaging of engrafted neural stem cells: its application in evaluating the optimal timing of transplantation for spinal cord injury. FASEB J 19 : 1839-1841, 2005 https://doi.org/10.1096/fj.05-4082fje
  39. 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 11 : 897-911, 2009 https://doi.org/10.3109/14653240903253857
  40. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, et al. : Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11 : 913-922, 2005 https://doi.org/10.1089/ten.2005.11.913
  41. Park JH, Kim DY, Sung IY, Choi GH, Jeon MH, Kim KK, et al. : Longterm results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery 70 : 1238-1247; discussion 1247, 2012 https://doi.org/10.1227/NEU.0b013e31824387f9
  42. Park JH, Min J, Baek SR, Kim SW, Kwon IK, Jeon SR : Enhanced neuroregenerative effects by scaffold for the treatment of a rat spinal cord injury with Wnt3a-secreting fibroblasts. Acta Neurochir (Wien) 155 : 809-816, 2013 https://doi.org/10.1007/s00701-013-1663-7
  43. Parr AM, Tator CH, Keating A : Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 40 : 609-619, 2007 https://doi.org/10.1038/sj.bmt.1705757
  44. Saberi H, Moshayedi P, Aghayan HR, Arjmand B, Hosseini SK, Emami-Razavi SH, et al. : Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett 443 : 46-50, 2008 https://doi.org/10.1016/j.neulet.2008.07.041
  45. 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 30 : 127-136, 2012
  46. Seo DK, Kim JH, Min J, Yoon HH, Shin ES, Kim SW, et al. : Enhanced axonal regeneration by transplanted Wnt3a-secreting human mesenchymal stem cells in a rat model of spinal cord injury. Acta Neurochir (Wien) 159 : 947-957, 2017 https://doi.org/10.1007/s00701-017-3097-0
  47. Shin JC, Kim KN, Yoo J, Kim IS, Yun S, Lee H, et al. : Clinical trial of human fetal brain-derived neural stem/progenitor cell transplantation in patients with traumatic cervical spinal cord injury. Neural Plast 2015 : 630932, 2015
  48. Shrestha B, Coykendall K, Li Y, Moon A, Priyadarshani P, Yao L : Repair of injured spinal cord using biomaterial scaffolds and stem cells. Stem Cell Res Ther 5 : 91, 2014 https://doi.org/10.1186/scrt480
  49. Silva NA, Sousa N, Reis RL, Salgado AJ : From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114 : 25-57, 2014 https://doi.org/10.1016/j.pneurobio.2013.11.002
  50. Stenudd M, Sabelstrom H, Frisen J : Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol 72 : 235-237, 2015 https://doi.org/10.1001/jamaneurol.2014.2927
  51. 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 15 : 675-687, 2006 https://doi.org/10.3727/000000006783464381
  52. Tashiro S, Nishimura S, Iwai H, Sugai K, Zhang L, Shinozaki M, et al. : Functional recovery from neural stem/progenitor cell transplantation combined with treadmill training in mice with chronic spinal cord injury. Sci Rep 6 : 30898, 2016 https://doi.org/10.1038/srep30898
  53. Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, et al. : Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A 99 : 3024-3029, 2002 https://doi.org/10.1073/pnas.052678899
  54. Tetzlaff W, Okon EB, Karimi-Abdolrezaee S, Hill CE, Sparling JS, Plemel JR, et al. : A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 28 : 1611-1682, 2011 https://doi.org/10.1089/neu.2009.1177
  55. Trounson A, McDonald C : Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17 : 11-22, 2015 https://doi.org/10.1016/j.stem.2015.06.007
  56. Ubiali F, Nava S, Nessi V, Frigerio S, Parati E, Bernasconi P, et al. : Allorecognition of human neural stem cells by peripheral blood lymphocytes despite low expression of MHC molecules: role of $TGF-{\beta}$ in modulating proliferation. Int Immunol 19 : 1063-1074, 2007 https://doi.org/10.1093/intimm/dxm079
  57. Ullah I, Subbarao RB, Rho GJ : Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 35 : e00191, 2015 https://doi.org/10.1042/BSR20150025
  58. Valverde F, Santacana M, Heredia M : Formation of an olfactory glomerulus: morphological aspects of development and organization. Neuroscience 49 : 255-275, 1992 https://doi.org/10.1016/0306-4522(92)90094-I
  59. Vaquero J, Zurita M, Rico MA, Bonilla C, Aguayo C, Montilla J, et al. : An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy 18 : 1025-1036, 2016 https://doi.org/10.1016/j.jcyt.2016.05.003
  60. Wakao S, Matsuse D, Dezawa M : Mesenchymal stem cells as a source of Schwann cells: their anticipated use in peripheral nerve regeneration. Cells Tissues Organs 200 : 31-41, 2014 https://doi.org/10.1159/000368188
  61. Xiao Z, Tang F, Zhao Y, Han G, Yin N, Li X, et al. : Significant improvement of acute complete spinal cord injury patients diagnosed by a combined criteria implanted with neuroregen scaffolds and mesenchymal stem cells. Cell Transplant 27 : 907-915, 2018 https://doi.org/10.1177/0963689718766279
  62. Yao R, Murtaza M, Velasquez JT, Todorovic M, Rayfield A, Ekberg J, et al. : Olfactory ensheathing cells for spinal cord injury: sniffing out the issues. Cell Transplant 27 : 879-889, 2018 https://doi.org/10.1177/0963689718779353
  63. Yoon HH, Min J, Shin N, Kim YH, Kim JM, Hwang YS, et al. : Are human dental papilla-derived stem cell and human brain-derived neural stem cell transplantations suitable for treatment of Parkinson's disease? Neural Regen Res 8 : 1190-1200, 2013
  64. 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 25 : 2066-2073, 2007 https://doi.org/10.1634/stemcells.2006-0807
  65. Young W : Electrical stimulation and motor recovery. Cell Transplant 24 : 429-446, 2015 https://doi.org/10.3727/096368915X686904
  66. Zeng X, Zeng YS, Ma YH, Lu LY, Du BL, Zhang W, et al. : Bone marrow mesenchymal stem cells in a three-dimensional gelatin sponge scaffold attenuate inflammation, promote angiogenesis, and reduce cavity formation in experimental spinal cord injury. Cell Transplant 20 : 1881-1899, 2011 https://doi.org/10.3727/096368911X566181
  67. Zhu H, Poon W, Liu Y, Leung GK, Wong Y, Feng Y, et al. : Phase I-II clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury. Cell Transplant 25 : 1925-1943, 2016 https://doi.org/10.3727/096368916X691411
  68. Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M : Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci U S A 103 : 13174-13179, 2006 https://doi.org/10.1073/pnas.0603747103

피인용 문헌

  1. INSPIRE Neuro-Spinal Scaffold™ : An Implantable Alternative to Stem-Cell Therapy for Endogenous Repair in Spinal Cord Injury vol.63, pp.5, 2020, https://doi.org/10.3340/jkns.2020.0003
  2. Influence of spinal cord injury on core regions of motor function vol.16, pp.3, 2020, https://doi.org/10.4103/1673-5374.293158