J Korean Med Assoc.  2011 May;54(5):468-481. 10.5124/jkma.2011.54.5.468.

Clinical applications of human neural stem cells in neurodegenerative diseases, especially neonatal hypoxic-ischemic brain injury and spinal cord injury

• Park KI

• KMID: 2190705
• DOI: http://doi.org/10.5124/jkma.2011.54.5.468

Abstract

Multipotent neural stem cells (NSCs) are operationally defined by their ability to self-renew, to differentiate into cells of all glial and neuronal lineages throughout the neuraxis, and to populate developing or degenerating CNS regions. The recognition that NSCs that were propagated in culture could be reimplanted into the mammalian brain, where they might integrate appropriately throughout the mammalian CNS and stably express foreign genes, has unveiled a new role for neural transplantation and gene therapy and a possible strategy for addressing the CNS manifestations of diseases that heretofore had been refractory to intervention. Proliferating single cells were isolated from the telencephalic region of human fetal cadavers at 13 weeks of gestation and were grown as neurospheres in long-term cultures. We investigated the characteristics of the growth, differentiation, and region-specific gene expression of human NSCs. An intriguing phenomenon with possible therapeutic potentials has begun to emerge from our observations of the behavior of NSCs in animal models of neonatal hypoxic-ischemic brain and spinal cord injury. During phases of active neurodegeneration, factors seem to be transiently elaborated to which NSCs may respond by migrating to degenerating regions and differentiating specifically towards replacement of dying neural cells. NSCs may attempt to repopulate and reconstitute ablated regions. In addition, NSCs may serve as vehicles for gene delivery and appear capable of simultaneous neural cell replacement and gene therapy. After the approval of the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine and Korean Food and Drug Administration, an investigator-sponsored clinical trial of the transplantation of human NSCs into patients with severe perinatal hypoxic ischemic brain injury and traumatic cervical motor complete spinal cord injury have been performed. The existing data from these clinical trials have shown to be safe, well tolerated, and of neurologically-some benefits.

Keyword

Neural stem cells; Hypoxic-ischemic brain injury; Spinal cord injuries; Cell therapy

MeSH Terms

Brain
Brain Injuries
Cadaver
Ethics Committees, Research
Gene Expression
Genetic Therapy
Humans
Models, Animal
Neural Stem Cells
Neurodegenerative Diseases
Neurons
Pregnancy
Spinal Cord
Spinal Cord Injuries
Tissue Therapy
Transplants
United States Food and Drug Administration

Reference

1. Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A. 1993. 90:2074–2077.

2. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994. 264:1145–1148.

3. Luskin MB. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron. 1993. 11:173–189.

4. Suhonen JO, Peterson DA, Ray J, Gage FH. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature. 1996. 383:624–627.

5. Gage FH. Mammalian neural stem cells. Science. 2000. 287:1433–1438.

6. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998. 4:1313–1317.

7. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992. 255:1707–1710.

8. Fowler CD, Liu Y, Wang Z. Estrogen and adult neurogenesis in the amygdala and hypothalamus. Brain Res Rev. 2008. 57:342–351.

9. Sohur US, Emsley JG, Mitchell BD, Macklis JD. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos Trans R Soc Lond B Biol Sci. 2006. 361:1477–1497.

10. Cameron HA, Dayer AG. New interneurons in the adult neocortex: small, sparse, but significant? Biol Psychiatry. 2008. 63:650–655.

11. Rakic P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci. 2002. 3:65–71.

12. Park KI, Teng YD, Snyder EY. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. 2002. 20:1111–1117.

13. Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY. 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. 2002. 99:3024–3029.

14. Ashton RS, Banerjee A, Punyani S, Schaffer DV, Kane RS. Scaffolds based on degradable alginate hydrogels and poly (lactide-co-glycolide) microspheres for stem cell culture. Biomaterials. 2007. 28:5518–5525.

15. Cullen DK, Stabenfeldt SE, Simon CM, Tate CC, LaPlaca MC. In vitro neural injury model for optimization of tissue-engineered constructs. J Neurosci Res. 2007. 85:3642–3451.

16. Tysseling-Mattiace VM, Sahni V, Niece KL, Birch D, Czeisler C, Fehlings MG, Stupp SI, Kessler JA. Self assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. J Neurosci. 2008. 28:3814–3823.

17. Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005. 436:266–271.

18. Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000. 3:537–544.

19. Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, Clark D, Rose H, Fu G, Clarke J, McKercher S, Meerloo J, Muller FJ, Park KI, Butters TD, Dwek RA, Schwartz P, Tong G, Wenger D, Lipton SA, Seyfried TN, Platt FM, Snyder EY. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007. 13:439–447.

20. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders: time for clinical translation? J Clin Invest. 2010. 120:29–40.

21. Kokovay E, Shen Q, Temple S. The incredible elastic brain: how neural stem cells expand our minds. Neuron. 2008. 60:420–429.

22. Study of HuCNS-SC cells in patients with infantile or late infantile Neuronal Ceroid Lipofuscinosis (NCL) [Internet]. updated 2010 Nov 5; cited 2011 Apr 29. Bethesda (MD): U. S. National Institute of Health;Available from: http://www.clinicaltrials.gov/ct2/show/NCT00337636?term-batten&rank=4.

23. Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell. 2008. 3:591–594.

24. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004. 207(Pt 18):3149–3154.

25. Dilenge ME, Majnemer A, Shevell MI. Long-term developmental outcome of asphyxiated term neonates. J Child Neurol. 2001. 16:781–792.

26. Sahni R, Sanocka UM. Hypothermia for hypoxic-ischemic encephalopathy. Clin Perinatol. 2008. 35:717–734. vi

27. Park KI, Hack MA, Ourednik J, Yandava B, Flax JD, Stieg PE, Gullans S, Jensen FE, Sidman RL, Ourednik V, Snyder EY. Acute injury directs the migration, proliferation, and differen-tiation of solid organ stem cells: evidence from the effect of hypoxia-ischemia in the CNS on clonal "reporter" neural stem cells. Exp Neurol. 2006. 199:156–178.

28. Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004. 101:18117–18122.

29. Park KI, Himes BT, Stieg PE, Tessler A, Fischer I, Snyder EY. Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment of Neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Exp Neurol. 2006. 199:179–190.

30. Bacigaluppi M, Pluchino S, Peruzzotti-Jametti L, Kilic E, Kilic U, Salani G, Brambilla E, West MJ, Comi G, Martino G, Hermann DM. Delayed post-ischaemic neuroprotection following sys-temic neural stem cell transplantation involves multiple mechanisms. Brain. 2009. 132(Pt 8):2239–2251.

31. Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, Hong NH, Kim JH, Ban JJ, Park HK, Kim SU, Park CG, Lee SK, Kim M, Roh JK. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2008. 131(Pt 3):616–629.

32. de Paula S, Greggio S, DaCosta JC. Use of stem cells in perinatal asphyxia: from bench to bedside. J Pediatr (Rio J). 2010. 86:451–464.

33. Pimentel-Coelho PM, Mendez-Otero R. Cell therapy for neo-natal hypoxic-ischemic encephalopathy. Stem Cells Dev. 2010. 19:299–310.

34. Cord blood for neonatal hypoxic-ischemic encephalopathy [Internet]. updated 2009 Oct 19; cited 2011 Apr 29. Bethesda (MD): U. S. National Institute of Health;Available from: http://www.clinicaltrials.gov/ct2/show/NCT00593242.

35. Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, Battistella V, Goldenberg RC, Kasai-Brunswick T, Chagas CL, Wajnberg E, Maiolino A, Salles Xavier S, Andre C, Mendez-Otero R, de Freitas GR. Migration and homing of bone-mar-row mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010. 221:122–128.

36. Correa PL, Mesquita CT, Felix RM, Azevedo JC, Barbirato GB, Falcao CH, Gonzalez C, Mendonça ML, Manfrim A, de Freitas G, Oliveira CC, Silva D, Avila D, Borojevic R, Alves S, Oliveira AC Jr, Dohmann HF. Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke. Clin Nucl Med. 2007. 32:839–841.

37. Lee JA, Kim BI, Jo CH, Choi CW, Kim EK, Kim HS, Yoon KS, Choi JH. Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res. 2010. 67:42–46.

38. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010. 24:387–393.

39. Janowski M, Walczak P, Date I. Intravenous route of cell delivery for treatment of neurological disorders: a meta-analy-sis of preclinical results. Stem Cells Dev. 2010. 19:5–16.

40. Stem Cell Therapies as an Emerging Paradigm in Stroke Participants. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009. 40:510–515.

41. Li L, Jiang Q, Ding G, Zhang L, Zhang ZG, Li Q, Panda S, Lu M, Ewing JR, Chopp M. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. J Cereb Blood Flow Metab. 2010. 30:653–662.

42. Bliss T, Guzman R, Daadi M, Steinberg GK. Cell transplantation therapy for stroke. Stroke. 2007. 38:2 Suppl. 817–826.

43. Borlongan CV. Cell therapy for stroke: remaining issues to address before embarking on clinical trials. Stroke. 2009. 40:3 Suppl. S146–S148.

44. Kim HT, Kim IS, Lee IS, Lee JP, Snyder EY, Park KI. Human neurospheres derived from the fetal central nervous system are regionally and temporally specified but are not committed. Exp Neurol. 2006. 199:222–235.

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

46. Nandoe Tewarie RS, Hurtado A, Bartels RH, Grotenhuis A, Oudega M. Stem cell-based therapies for spinal cord injury. J Spinal Cord Med. 2009. 32:105–114.

47. Sahni V, Kessler JA. Stem cell therapies for spinal cord injury. Nat Rev Neurol. 2010. 6:363–372.

48. 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. 2003. 181:115–129.

49. Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A. 2005. 102:14069–14074.

50. Hofstetter CP, Holmström NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisén J, Olson L. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005. 8:346–353.

51. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005. 25:4694–4705.

52. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG. Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci. 2006. 26:3377–3389.

53. Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M. Synergy between immunecells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci U S A. 2006. 103:13174–13179.

54. Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ. Human neural stem cells differentiate and promote loco-motor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS One. 2010. 5:e12272.

55. Hooshmand MJ, Sontag CJ, Uchida N, Tamaki S, Anderson AJ, Cummings BJ. Analysis of host-mediated repair mecha-nisms after human CNS-stem cell transplantation for spinal cord injury: correlation of engraftment with recovery. PLoS One. 2009. 4:e5871.

56. Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, Koliatsos VE. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med. 2007. 4:e39.

57. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, Ellaway PH, Fehlings MG, Guest JD, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Short D, Nakamura M, Coleman WP, Gaviria M, Privat A. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord. 2007. 45:206–221.

58. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, Bartlett PF, Blight AR, Dietz V, Ditunno J, Dobkin BH, Havton LA, Ellaway PH, Fehlings MG, Privat A, Grossman R, Guest JD, Kleitman N, Nakamura M, Gaviria M, Short D. 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. 2007. 45:190–205.

59. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, Ditunno JF, Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Blight AR, Dobkin BH, Grossman R, Katoh H, Privat A, Kalichman M. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord. 2007. 45:232–242.

60. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, Curt A, Ditunno JF, Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Privat A. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord. 2007. 45:222–231.

61. Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, Geraghty T, Mackay-Sim A. Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain. 2005. 128(Pt 12):2951–2960.

62. Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer R, Marder JB, Yoles E, Belkin M, Schwartz M, Hadani M. Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine. 2005. 3:173–181.

63. Moviglia GA, Fernandez Vina R, Brizuela JA, Saslavsky J, Vrsalovic F, Varela G, Bastos F, Farina P, Etchegaray G, Barbieri M, Martinez G, Picasso F, Schmidt Y, Brizuela P, Gaeta CA, Costanzo H, Moviglia Brandolino MT, Merino S, Pes ME, Veloso MJ, Rugilo C, Tamer I, Shuster GS. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy. 2006. 8:202–209.

64. Sykova E, Homola A, Mazanec R, Lachmann H, Konradova SL, Kobylka P, Padr R, Neuwirth J, Komrska V, Vavra V, Stulik J, Bojar M. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006. 15:675–687.

65. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR, Min BH, Kim EY, Choi BH, Park H, Ha Y. 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.

66. Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH, Montenegro X, Gonzalez R, Silva F. 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. 17:1277–1293.

67. Mackay-Sim A, Feron F, Cochrane J, Bassingthwaighte L, Bayliss C, Davies W, Fronek P, Gray C, Kerr G, Licina P, Nowitzke A, Perry C, Silburn PA, Urquhart S, Geraghty T. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain. 2008. 131(Pt 9):2376–2386.

68. Saberi H, Moshayedi P, Aghayan HR, Arjmand B, Hosseini SK, Emami-Razavi SH, Rahimi-Movaghar V, Raza M, Firouzi M. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett. 2008. 443:46–50.

69. Lima C, Escada P, Pratas-Vital J, Branco C, Arcangeli CA, Lazzeri G, Maia CA, Capucho C, Hasse-Ferreira A, Peduzzi JD. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010. 24:10–22.

70. Lithium and cord blood cell for spinal cord injury [Internet]. cited 2011 Apr 11. Wanchai: Chinese Spinal Cord Injury Network;Available from: http://www.chinascinet.org/index.php?option=com_content&task=view&id=31&Itemid=57.