Skip to main content

Advertisement

SpringerLink
Log in

Intracerebroventricular Transplantation of Human Mesenchymal Stem Cells Induced to Secrete Neurotrophic Factors Attenuates Clinical Symptoms in a Mouse Model of Multiple Sclerosis

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Stem cell-based therapy holds great potential for future treatment of multiple sclerosis (MS). Bone marrow mesenchymal stem cells (MSCs) were previously reported to ameliorate symptoms in mouse MS models (experimental autoimmune encephalomyelitis, EAE). In this study, we induced MSCs to differentiate in vitro into neurotrophic factor-producing cells (NTFCs). Our main goal was to examine the clinical use of NTFCs on EAE symptoms. The NTFCs and MSCs were transplanted intracerebroventricularly (ICV) to EAE mice. We found that NTFCs transplantations resulted in a delay of symptom onset and increased animal survival. Transplantation of MSCs also exerted a positive effect but to a lesser extent. In vitro analysis demonstrated the NTFCs' capacity to suppress mice immune cells and protect neuronal cells from oxidative insult. Our results indicate that NTFCs-transplanted ICV delay disease symptoms of EAE mice, possibly via neuroprotection and immunomodulation, and may serve as a possible treatment to MS.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822

    Article  CAS  PubMed  Google Scholar 

  • Archer D, Cuddon P, Lipsitz D, Duncan I (1997) Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nat Med 3:54–59

    Article  CAS  PubMed  Google Scholar 

  • Bahat-Stroomza M, Barhum Y, Levy YS, Karpov O, Bulvik S, Melamed E, Offen D (2009) Induction of adult human bone marrow mesenchymal stromal cells into functional astrocyte-like cells: potential for restorative treatment in Parkinson's disease. J Mol Neurosci 39:199–210

    Article  CAS  PubMed  Google Scholar 

  • Barzilay R, Levy SY, Melamed E, Offen D (2006) Adult stem cells for neuronal repair. Isr Med Assoc J 8:61–66

    PubMed  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  CAS  PubMed  Google Scholar 

  • Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, Sancricca C, Nociti V, Tonali PA, Mirabella M (2006) Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy. Clin Immunol 118:77–82

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Katakowski M, Li Y, Lu D, Wang L, Zhang L, Chen J, Xu Y, Gautam S, Mahmood A, Chopp M (2002) Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 59:687–691

    Article  Google Scholar 

  • Dominici M, Le-Blanc K, Mueller I, Slaper-Conterbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  PubMed  Google Scholar 

  • Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, Lavon I, Baniyash M, Lassman H, Ben-Hur T (2007) Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 61:209–218

    Article  CAS  PubMed  Google Scholar 

  • Fibbe WE, Nauta AJ, Roelofs H (2007) Modulation of immune responses by mesenchymal stem cells. Ann N Y Acad Sci 1106:278

    Article  Google Scholar 

  • Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A (2007) Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61:219–227

    Article  CAS  PubMed  Google Scholar 

  • Gordon D, Pavloyska G, Glover CP, Uney JB, Wraith D, Scolding NJ (2008) Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration. Neurosci Lett 448:71–73

    Article  CAS  PubMed  Google Scholar 

  • Hellman 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  Google Scholar 

  • Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung H (2006) Immunopathogenesis and immunotherapy of multiple sclerosis. Nature Clinical Practice Neurology 2:201–211

    Article  CAS  PubMed  Google Scholar 

  • Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483–3493

    Article  CAS  PubMed  Google Scholar 

  • Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D (2008) Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 65:753–761

    Article  PubMed  Google Scholar 

  • Keirstead HS (2005) Stem cells for the treatment of myelin loss. Trends Neurosci 28:677–683

    CAS  PubMed  Google Scholar 

  • Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262:509–525

    Article  PubMed  Google Scholar 

  • Lianhua B, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD, Miller RH (2009) Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57:1192–1203

    Article  Google Scholar 

  • Loeb JA (2007) Neuroprotection and repair by neurotrophic and gliotrophic factors in multiple sclerosis. Neurology 68:S38–S42

    Article  CAS  PubMed  Google Scholar 

  • Makar TK, Trisler D, Bever CT, Goolsby JE, Sura KT, Balasubramanian S, Sultana S, Patel N, Ford D, Singh IS, Gupta A, Valenzuela RM, Dhib-Jalbut S (2008a) Stem cell based delivery of IFN-[beta] reduces relapses in experimental autoimmune encephalomyelitis. J Neuroimmunol 196:67–81

    Article  CAS  PubMed  Google Scholar 

  • Makar TK, Trisler D, Sura KT, Sultana S, Patel N, Bever CT (2008b) Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis. J Neurol Sci 270:70–76

    Article  CAS  PubMed  Google Scholar 

  • Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952

    Article  CAS  PubMed  Google Scholar 

  • Offen D, Gilgun-Sherki Y, Barhum Y, Benhar M, Grinberg L, Reich R, Melamed E, Atlas D (2004) A novel low molecular weight antioxidant crosses the blood brain barrier and attenuates experimental autoimmune encephalomyelitis. J Neurochem 89:1241–1251

    Article  CAS  PubMed  Google Scholar 

  • Payne N, Siatskas C, Bernard CCA (2008) The promise of stem cell and regenerative therapies for multiple sclerosis. J Autoimmun 31:288–294

    Article  CAS  PubMed  Google Scholar 

  • Pisati F, Bossolasco P, Meregalli M, Cova L, Belicchi M, Gavina M, Marchesi C, Calzarossa C, Soligo D, Lambertenghi-Deliliers G, Bresolin N, Silani V, Torrente Y, Polli E (2007) Induction of neurotrophin expression via human adult mesenchymal stem cells: implication for cell therapy in neurodegenerative diseases. Cell Transplant 16:41–55

    PubMed  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  CAS  PubMed  Google Scholar 

  • Pluchino S, Martino G (2005) The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci 233:117–119

    Article  CAS  PubMed  Google Scholar 

  • Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688–694

    Article  CAS  PubMed  Google Scholar 

  • 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 (2005) Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436:266–271

    Article  CAS  PubMed  Google Scholar 

  • Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, Charbord P, Domenech J (2007) The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 25:1737–1745

    Article  CAS  PubMed  Google Scholar 

  • Ringe J, Strassburg S, Neuman K, Endres M, Notter M, Gerd-Rudiger B, Kaps C, Sittinger M (2007) Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem 101:135–146

    Article  CAS  PubMed  Google Scholar 

  • Sadan O, Shemesh N, Barzilay R, Bahat-Stromza M, Melamed E, Cohen Y, Offen D (2008) Migration of neurotrophic factors-secreting mesenchymal stem cells towards a quinolinic acid lesion as viewed by MRI. Stem Cells 26:2542–2551

    Article  CAS  PubMed  Google Scholar 

  • Sadan O, Bahat-Stroomza M, Barhum Y, Levy YS, Pisneysky A, Peretz H, Bar Ilan A, Bulvik S, Shemesh N, Krepel D, Cohen Y, Melamed E, Offen E (2009) Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease. Stem Cells Dev 18(8):1179–1190

    Article  CAS  PubMed  Google Scholar 

  • Triaca V, Tirassa P, Aloe L (2005) Presence of nerve growth factor and TrkA expression in the SVZ of EAE rats: evidence for a possible functional significance. Exp Neurol 191:53–64

    Article  CAS  PubMed  Google Scholar 

  • Uccelli A, Moretta L, Pistoia V (2006) Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 36:2566–2573

    Article  CAS  PubMed  Google Scholar 

  • Whitham RH, Bourdette DN, Hashim GA, Herndon RM, Ilg RC, Vandenbark AA, Offner H (1991) Lymphocytes from SJL/J mice immunized with spinal cord respond selectively to a peptide of proteolipid protein and transfer relapsing demyelinating experimental autoimmune encephalomyelitis. J Immunol 146:101–107

    CAS  PubMed  Google Scholar 

  • Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761

    Article  CAS  PubMed  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. Exp Neurol 195:16–26

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Ziemssen T, Kumpfel T, Klinkert WEF, Neuhaus O, Hohlfeld R (2002) Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain 125:2381–2391

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

The work presented in this manuscript was supported, in part, by the Norma and Alan Aufzein Chair for Parkinson’s Disease Research.

Author information

Authors and Affiliations

  1. Felsenstein Medical Research Center, Tel Aviv University, Sackler School of Medicine, Petach Tikva, 49100, Israel

    Yael Barhum, Sharon Gai-Castro, Merav Bahat-Stromza, Ran Barzilay, Eldad Melamed & Daniel Offen

Authors
  1. Yael Barhum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon Gai-Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Merav Bahat-Stromza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ran Barzilay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eldad Melamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Offen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Offen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barhum, Y., Gai-Castro, S., Bahat-Stromza, M. et al. Intracerebroventricular Transplantation of Human Mesenchymal Stem Cells Induced to Secrete Neurotrophic Factors Attenuates Clinical Symptoms in a Mouse Model of Multiple Sclerosis. J Mol Neurosci 41, 129–137 (2010). https://doi.org/10.1007/s12031-009-9302-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-009-9302-8

Keywords

Search

Navigation