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Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease

  • D. Offen
  • Y. Barhum
  • Y.-S. Levy
  • A. Burshtein
  • H. Panet
  • T. Cherlow
  • E. Melamed
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 72)

Abstract

Strategies of cell therapy for the treatment of Parkinson’s disease (PD) are focused on replacing damaged neurons with cells to restore or improve function that is impaired due to cell population damage. In our studies, we used mesenchymal stromal cells (MSCs) from mouse bone marrow. Following our novel neuronal differentiation method, we found that the basic cellular phenotype changed to cells with neural morphology that express specific markers including those characteristic for dopaminergic neurons, such as tyrosine hydroxylase (TH). Intrastriatal transplantation of the differentiated MSCs in 6-hydroxydopamine-lesioned mice led to marked reduction in the amphetamine-induced rotations. Immunohistological analysis of the mice brains four months post transplantation, demonstrated that most of the transplanted cells survived in the striatum and expressed TH. Some of the TH positive cells migrated toward the substantia nigra. In conclusion, transplantation of bone marrow derived stem cells differentiated to dopaminergic-like cells, successfully improved behavior in an animal model of PD suggesting an accessible source of cells that may be used for autotransplantation in patient with PD.

Keywords

Multipotent mesenchymal stromal cells (MSCs) dopamine dopaminergic neurons Parkinson’s disease (PD) stem cells 

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References

  1. Akerud P, Canalsl JM, Snyder EY, Arenas E (2001) Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson’s disease. J Neurosci 21: 8108–8118PubMedGoogle Scholar
  2. Arnhold S, Klein H, Klinz FJ, Absenger Y, Schmidt A, Schinkothe T, Brixius K, Kozlowski J, Desai B, Bloch W, Addicks K (2006) Human bone marrow stroma cells display certain neural characteristics and integrate in the subventricular compartment after injection into the liquor system. Eur J Cell Biol 85: 551–565PubMedCrossRefGoogle Scholar
  3. Baddoo M, Hill K, Wilkinson R, Gaupp D, Hughes C, Kopen GC, Phinney DG (2003) Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection. J Cell Biochem 89: 1235–1249PubMedCrossRefGoogle Scholar
  4. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L (2003) Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in Parkinsonian mice. Nat Biotechnol 21: 1200–1207PubMedCrossRefGoogle Scholar
  5. Ben-Hur T, Idelson M, Khaner H, Pera M, Reinhartz E, Itzik A, Reubinoff BE (2004) Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 22: 1246–1255PubMedCrossRefGoogle Scholar
  6. Bianco P, Robey PG (2000) Marrow stromal stem cells. J Clin Invest 105: 1663–1668PubMedGoogle Scholar
  7. Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal cells: Nature, biology, and potential application. Stem Cells 19: 180–192PubMedCrossRefGoogle Scholar
  8. Björklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99: 2344–2349PubMedCrossRefGoogle Scholar
  9. Blondheim NR, Levy YS, Ben-Zur T, Burshtein A, Cherlow T, Kan I, Barzilai R, Bahat-Stromza M, Barhum Y, Bulvik S, Melamed E, Offen D (2006) Human mesenchymal stem cells express neural genes, suggesting a neural predisposition. Stem Cells Dev 15: 141–164PubMedCrossRefGoogle Scholar
  10. Bottenstein JE (1985) Growth of neural cells in defined media. In: Bottenstein JE, Sato G (eds) Cell culture in the neurosciences. Plenum Press, New York, pp 1–40Google Scholar
  11. Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, Morizane A, Bergquist F, Riebe I, Nannmark U, Carta M, Hanse E, Takahashi J, Sasai Y, Funa K, Brundin P, Eriksson PS, Li JY (2006) Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 24: 1433–1440PubMedCrossRefGoogle Scholar
  12. Carman LS, Gage FH, Shults CW (1991) Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior. Brain Res 553: 275–283PubMedCrossRefGoogle Scholar
  13. Carson CT, Aigner S, Gage FH (2006) Stem cells: the good, bad and barely in control. Nat Med 12: 1237–1238PubMedCrossRefGoogle Scholar
  14. Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73: 778–786PubMedCrossRefGoogle Scholar
  15. Chen Q, Long Y, Yuan X, Zou L, Sun J, Chen S, Perez-Polo 1R, Yang K (2005) Protective effects of bone marrow stromal cell transplantation in injured rodent brain: synthesis of neurotrophic factors. J Neurosci Res 80: 611–619PubMedCrossRefGoogle Scholar
  16. Colter DC, Class R, DiGirolamo CM, Prockop Dl (2000) Rapid expansion of recycling stem cells cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci USA 97: 3213–3218PubMedCrossRefGoogle Scholar
  17. Deans RJ, Moseley AB (2000) Mesenchymal stem cells: Biology and potential clinical use. Exp Hematol 28: 875–884PubMedCrossRefGoogle Scholar
  18. Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C (2004) Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113: 1701–1710PubMedCrossRefGoogle Scholar
  19. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315–317PubMedCrossRefGoogle Scholar
  20. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344: 710–719PubMedCrossRefGoogle Scholar
  21. Hadjantonakis AK, Gertsenstein M, Ikawa M, Okabe M, Nagy A (1998) Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech Dev 76: 79–90PubMedCrossRefGoogle Scholar
  22. Hagell P, Piccini P, Bjorklund A, Brundin P, Rehncrona S, Widner H, Crabb L, Pavese N, Oertel WH, Quinn N, Brooks DJ, Lindvall O (2002) Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci 5: 627–628PubMedGoogle Scholar
  23. Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 18: 1407–1418CrossRefGoogle Scholar
  24. Hefti F, Enz A, Melamed E (1982) Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs. Neuropharmacology 24: 19–23CrossRefGoogle Scholar
  25. Hellmann MA, Panet H, Barhum Y, Melamed E, Offen D (2006) Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents. Neurosci Lett 395: 124–128PubMedCrossRefGoogle Scholar
  26. Hudson JL, Craig VHG, Stromberg I, Brock S, Clayton J, Masserano J, Hoffer BJ, Gerhardt GA (1993) Correlation of apomorphine and amphetamine-induced turning with nigrostriatal dopamine content in inilateral 6-hydroxydopamine lesioned rats. Brain Res 626: 167–174PubMedCrossRefGoogle Scholar
  27. Jackson-Lewis V, Liberatore G (2000) Effects of a unilateral stereotaxic injection of Tinuvin 123 into the substantia nigra on the nigrostriatal dopaminergic pathway in the rat. Brain Res 866: 197–210PubMedCrossRefGoogle Scholar
  28. Kan I, Melamed E, Offen D (2005) Integral therapeutic potential of bone marrow mesechymal stem cells. Curr Drug Targets 6: 31–41PubMedCrossRefGoogle Scholar
  29. Kan I, Melamed E, Offen D, Green P (2007) Docosahexaenoic acid and arachidonic acid are fundamental supplements for induction of neuronal differentiation. J Lipid Res 48: 513–517PubMedCrossRefGoogle Scholar
  30. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S, Nishikawa SI, Sasai Y (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28: 31–40PubMedCrossRefGoogle Scholar
  31. Kim DW, Chung S, Hwang M et al. (2006) Stromal cell-derived inducing activity, nurrl, and signaling molecules synergistically induce dopaminergic neurons from mouse embryonic stem cells. Stem Cells 24: 557–567PubMedCrossRefGoogle Scholar
  32. Kim 1H, Auerbach JM, Rodríguez-Gómez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418: 50–56PubMedCrossRefGoogle Scholar
  33. Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease: Pathophysiologic and clinical implications. N Engl J Med 318: 876–880PubMedCrossRefGoogle Scholar
  34. Krause DS (2002) Plasticity of marrow-derived stem cells. Gene Ther 9: 754–758PubMedCrossRefGoogle Scholar
  35. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD (2000) Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 18: 675–679PubMedCrossRefGoogle Scholar
  36. Levy YS, Merims D, Panet H, Barhum Y, Melamed E, Offen D (2003) Induction of neuron-specific enolase promoter and neuronal markers in differentiated mouse bone marrow stromal cells. J Mol Neurosci 21: 127–138CrossRefGoogle Scholar
  37. Levy YS, Stroomza M, Melamed E, Offen D (2004) Embryonic and adult stem cells as a source for therapy in Parkinson’s disease. J Mol Neurosci24: 353–386PubMedCrossRefGoogle Scholar
  38. Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M (2001) Intracerebral transplantation of bone marrow stromal cells in a l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neurosci Lett 316: 67–70PubMedCrossRefGoogle Scholar
  39. Lindvall O, Bjorklund A (2004) Cell therapy in Parkinson’s disease. NeuroRx 1: 382–393PubMedCrossRefGoogle Scholar
  40. Mahmood A, Lu D, Yi L, Chen JL, Chopp M (2001) Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats. J Neurosurg 94: 589–595PubMedCrossRefGoogle Scholar
  41. Mahmood A, Lu D, Qu C, Goussev A, Chopp M (2005) Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery 57: 1026–1031PubMedCrossRefGoogle Scholar
  42. Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, Testa L, Livigni S, Fagioli F (2006) Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res 28: 523–526PubMedCrossRefGoogle Scholar
  43. Munoz-Elias G, Marcus AJ, Coyne TM, Woodbury D, Black IB (2004) Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J Neurosci 24: 4585–4595PubMedCrossRefGoogle Scholar
  44. Olanow CW, Goetz CG, Kordower JH et al. (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54: 403–414PubMedCrossRefGoogle Scholar
  45. Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, Ko JY, Koh HC, Kang Ml, Kang JS, Rhie DJ, Lee YS, Son H, Moon SY, Kim KS, Lee SH (2005) In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 92: 1265–1276PubMedCrossRefGoogle Scholar
  46. Pavon N, Vidal L, Alvarez P, Blanco L, Torres A, Rodriguez A, Macias R (1998) Behavioral evaluation of the unilateral lesion model in rats using 6-hydroxydopamine. Correlation between the rotations induced by d-amphetamine, apomorphine and the manual dexterity test. Rev Neurol 26: 915–918PubMedGoogle Scholar
  47. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
  48. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ (2004) Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103: 1662–1668PubMedCrossRefGoogle Scholar
  49. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147PubMedCrossRefGoogle Scholar
  50. Piccini P, Brooks D, Björklund A et al. (1999) Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci 2: 1137–1140PubMedCrossRefGoogle Scholar
  51. Prockop DJ (1997) Marrow stromal cells as stem cells for non-hematopoietic tissues. Science 276: 71–74PubMedCrossRefGoogle Scholar
  52. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 12: 1259–1268PubMedCrossRefGoogle Scholar
  53. Sanchez-Pernaute R, Studer L, Bankiewicz KS et al. (2001) In vitro generation and transplantation of precursor-derived human dopamine neurons. J Neurosci Res 65: 284–288PubMedCrossRefGoogle Scholar
  54. Sanchez-Pernaute R, Studer L, Ferrari D, Perrier A, Lee H, Vinuela A, Isacson O (2005) Long-term survival of dopamine neurons derived from parthenogenetic primate embryonic stem cells (cyno-1) after transplantation. Stem Cells 23: 914–922PubMedCrossRefGoogle Scholar
  55. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164: 247–256PubMedCrossRefGoogle Scholar
  56. Seyfried D, Ding J, Han Y, Li Y, Chen J, Chopp M (2006) Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg 104: 313–318PubMedGoogle Scholar
  57. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007) Therapeutic benefit of bone marrow stromal cells administered J month after stroke. J Cereb Blood Flow Metab 27: 6–13PubMedCrossRefGoogle Scholar
  58. Studer L, Tabar V, McKay RD (1998) Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1: 290–295PubMedCrossRefGoogle Scholar
  59. Takagi Y, Takahashi J, Saiki H, Morizane A, Hayashi T, Kishi Y, Fukuda H, Okamoto Y, Koyanagi M, Ideguchi M, Hayashi H, Imazato T, Kawasaki H, Suemori H, Omachi S, Iida H, Itoh N, Nakatsuji N, Sasai Y, Hashimoto N (2005) Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 115: 102–109PubMedCrossRefGoogle Scholar
  60. Thomas J, Wang J, Takubo H, Sheng J, de Jesus S, Bankiewicz KS (1994) A 6-hydroxydopamine-induced selective parkinsonian rat model: further biochemical and behavioral characterization. Exp Neurol 126: 159–167PubMedCrossRefGoogle Scholar
  61. Winkler C, Kirik D, Bjorklund A (2005) Cell transplantation in Parkinson’s disease: how can we make it work? Trends Neurosci 28: 86–92PubMedCrossRefGoogle Scholar
  62. Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61: 364–370PubMedCrossRefGoogle Scholar
  63. Yan Y, Yang D, Zarnowska ED et al. (2005) Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23(6): 781–790PubMedCrossRefGoogle Scholar
  64. Zeng X, Cai J, Chen J, Luo Y, You ZB, Fotter E, Wang Y, Harvey B, Miura T, Backman C, Chen GJ, Rao MS, Freed WJ (2004) Dopaminergic differentiation of human embryonic stem cells. Stem Cells 22: 925–940PubMedCrossRefGoogle Scholar
  65. Zhang J, Li Y, Chen J, Cui Y, Lu M, Elias SB, Mitchell JB, Hammill L, Vanguri P, Chopp M (2005) Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Ex-Neurol 195: 16–26CrossRefGoogle Scholar
  66. Zhang J, Li Y, Lu M, Cui Y, Chen J, Noffsinger L, Elias SB, Chopp M (2006) Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J Neurosci Res 84: 587–595PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • D. Offen
    • 1
    • 2
  • Y. Barhum
    • 2
  • Y.-S. Levy
    • 2
  • A. Burshtein
    • 2
  • H. Panet
    • 2
  • T. Cherlow
    • 2
  • E. Melamed
    • 2
    • 3
  1. 1.Felsenstein Medical Research Center, Beilinson CampusTel Aviv University, Rabin Medical CenterIsrael
  2. 2.Laboratory of Neurosciences, Felsenstein Medical Research Center, Sackler Faculty of MedicineTel Aviv University, Tel AvivIsrael
  3. 3.Department of NeurologyRabin Medical CenterPetah TiqvaIsrael

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