Skip to main content
SpringerLink
Log in
Book cover

Neuropsychiatric Disorders An Integrative Approach pp 133–143Cite as

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

  • Conference paper

Part of the book series: Journal of Neural Transmission. Supplementa ((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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • 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: 8108–8118

    PubMed  CAS  Google Scholar 

  • 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: 551–565

    Article  PubMed  CAS  Google Scholar 

  • 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: 1235–1249

    Article  PubMed  CAS  Google Scholar 

  • 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: 1200–1207

    Article  PubMed  CAS  Google Scholar 

  • 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: 1246–1255

    Article  PubMed  Google Scholar 

  • Bianco P, Robey PG (2000) Marrow stromal stem cells. J Clin Invest 105: 1663–1668

    PubMed  CAS  Google Scholar 

  • Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal cells: Nature, biology, and potential application. Stem Cells 19: 180–192

    Article  PubMed  CAS  Google Scholar 

  • 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: 2344–2349

    Article  PubMed  CAS  Google Scholar 

  • 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: 141–164

    Article  PubMed  CAS  Google Scholar 

  • 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 1–40

    Google Scholar 

  • 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: 1433–1440

    Article  PubMed  CAS  Google Scholar 

  • Carman LS, Gage FH, Shults CW (1991) Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior. Brain Res 553: 275–283

    Article  PubMed  CAS  Google Scholar 

  • Carson CT, Aigner S, Gage FH (2006) Stem cells: the good, bad and barely in control. Nat Med 12: 1237–1238

    Article  PubMed  CAS  Google Scholar 

  • 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: 778–786

    Article  PubMed  CAS  Google Scholar 

  • 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: 611–619

    Article  PubMed  CAS  Google Scholar 

  • 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: 3213–3218

    Article  PubMed  CAS  Google Scholar 

  • Deans RJ, Moseley AB (2000) Mesenchymal stem cells: Biology and potential clinical use. Exp Hematol 28: 875–884

    Article  PubMed  CAS  Google Scholar 

  • 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: 1701–1710

    Article  PubMed  CAS  Google Scholar 

  • 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: 315–317

    Article  PubMed  CAS  Google Scholar 

  • 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: 710–719

    Article  PubMed  CAS  Google Scholar 

  • 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: 79–90

    Article  PubMed  CAS  Google Scholar 

  • 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: 627–628

    PubMed  CAS  Google Scholar 

  • 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: 1407–1418

    Article  Google Scholar 

  • 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: 19–23

    Article  Google Scholar 

  • 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: 124–128

    Article  PubMed  CAS  Google Scholar 

  • 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: 167–174

    Article  PubMed  CAS  Google Scholar 

  • 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: 197–210

    Article  PubMed  CAS  Google Scholar 

  • Kan I, Melamed E, Offen D (2005) Integral therapeutic potential of bone marrow mesechymal stem cells. Curr Drug Targets 6: 31–41

    Article  PubMed  CAS  Google Scholar 

  • 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: 513–517

    Article  PubMed  CAS  Google Scholar 

  • 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: 31–40

    Article  PubMed  CAS  Google Scholar 

  • 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: 557–567

    Article  PubMed  CAS  Google Scholar 

  • 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: 50–56

    Article  PubMed  CAS  Google Scholar 

  • 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: 876–880

    Article  PubMed  CAS  Google Scholar 

  • Krause DS (2002) Plasticity of marrow-derived stem cells. Gene Ther 9: 754–758

    Article  PubMed  CAS  Google Scholar 

  • 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: 675–679

    Article  PubMed  CAS  Google Scholar 

  • 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: 127–138

    Article  Google Scholar 

  • 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: 353–386

    Article  PubMed  CAS  Google Scholar 

  • 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: 67–70

    Article  PubMed  CAS  Google Scholar 

  • Lindvall O, Bjorklund A (2004) Cell therapy in Parkinson’s disease. NeuroRx 1: 382–393

    Article  PubMed  Google Scholar 

  • 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: 589–595

    Article  PubMed  CAS  Google Scholar 

  • 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: 1026–1031

    Article  PubMed  Google Scholar 

  • 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: 523–526

    Article  PubMed  Google Scholar 

  • 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: 4585–4595

    Article  PubMed  CAS  Google Scholar 

  • 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: 403–414

    Article  PubMed  Google Scholar 

  • 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: 1265–1276

    Article  PubMed  CAS  Google Scholar 

  • 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: 915–918

    PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego

    Google Scholar 

  • 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: 1662–1668

    Article  PubMed  CAS  Google Scholar 

  • 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: 143–147

    Article  PubMed  CAS  Google Scholar 

  • 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: 1137–1140

    Article  PubMed  CAS  Google Scholar 

  • Prockop DJ (1997) Marrow stromal cells as stem cells for non-hematopoietic tissues. Science 276: 71–74

    Article  PubMed  CAS  Google Scholar 

  • 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: 1259–1268

    Article  PubMed  CAS  Google Scholar 

  • 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: 284–288

    Article  PubMed  CAS  Google Scholar 

  • 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: 914–922

    Article  PubMed  Google Scholar 

  • 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: 247–256

    Article  PubMed  CAS  Google Scholar 

  • 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: 313–318

    PubMed  Google Scholar 

  • 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: 6–13

    Article  PubMed  CAS  Google Scholar 

  • Studer L, Tabar V, McKay RD (1998) Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1: 290–295

    Article  PubMed  CAS  Google Scholar 

  • 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: 102–109

    Article  PubMed  CAS  Google Scholar 

  • 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: 159–167

    Article  PubMed  CAS  Google Scholar 

  • Winkler C, Kirik D, Bjorklund A (2005) Cell transplantation in Parkinson’s disease: how can we make it work? Trends Neurosci 28: 86–92

    Article  PubMed  CAS  Google Scholar 

  • Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61: 364–370

    Article  PubMed  CAS  Google Scholar 

  • Yan Y, Yang D, Zarnowska ED et al. (2005) Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23(6): 781–790

    Article  PubMed  CAS  Google Scholar 

  • 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: 925–940

    Article  PubMed  CAS  Google Scholar 

  • 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: 16–26

    Article  CAS  Google Scholar 

  • 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: 587–595

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Felsenstein Medical Research Center, Beilinson Campus, Tel Aviv University, Rabin Medical Center, Petah Tikva, 49100, Israel

    D. Offen Ph.D.

  2. Laboratory of Neurosciences, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    D. Offen Ph.D., Y. Barhum, Y.-S. Levy, A. Burshtein, H. Panet, T. Cherlow & E. Melamed

  3. Department of Neurology, Rabin Medical Center, Petah Tiqva, Israel

    E. Melamed

Authors
  1. D. Offen Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Barhum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y.-S. Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Burshtein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Panet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Cherlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Melamed
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und Psychotherapie, Würzburg, Germany

    M. Gerlach

  2. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Würzburg, Germany

    Jürgen Deckert

  3. Prince of Wales Medical Research Institute, Sydney, Australia

    K. Double

  4. Institut für Virologie und Immunobiologie, Würzburg, Germany

    E. Koutsilieri

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag

About this paper

Cite this paper

Offen, D. et al. (2007). Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease. In: Gerlach, M., Deckert, J., Double, K., Koutsilieri, E. (eds) Neuropsychiatric Disorders An Integrative Approach. Journal of Neural Transmission. Supplementa, vol 72. Springer, Vienna. https://doi.org/10.1007/978-3-211-73574-9_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-211-73574-9_16

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-73573-2

  • Online ISBN: 978-3-211-73574-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation