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Comparative Effects between Bone Marrow and Mesenchymal Stem Cell Transplantation in GDNF Expression and Motor Function Recovery in a Motorneuron Degenerative Mouse Model

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Abstract

Motorneuron degenerative diseases, such as amyotrophic lateral sclerosis (ALS), are characterized by the progressive and rapid loss of motor neurons in the brain and spinal cord, leading to paralysis and death. GDNF (glial cell line derived neurotrophic factor) has been previously shown to be capable of protecting motor-neurons in ALS animal models although its delivery to the spinal cord after systemic administration is blocked by the blood brain barrier. Thus, it is necessary to develop new neurotrophic approaches to protect these motor neurons from death. Bone marrow-derived stem cells have been shown to be capable of improving a large variety of neurodegenerative disorders through neurotrophic mediated mechanisms. Here we analyzed the effect of transplanting whole bone marrow or cultured mesenchymal stem cells into the spinal cord of a motor neuron degenerative mouse model. Motor functions were analyzed using various behavior tests for several weeks after transplantation. We observed that bone marrow, and to a lesser degree mesenchymal stem cell, treated mice improved significantly in the motor tests performed, coinciding with a higher GDNF immunoreactivity in the grafted spinal cord. In several cases, the treated spinal cords were extracted, the engrafted bone marrow cells isolated and cultured, and finally re-transplanted into the spleen of immunodeficient mice. Re-grafted cells were detected in the host spleen, bloodstream and bone marrow, demonstrating a phenotypic stability. Thus, bone marrow cells do not suffer significant phenotypic modifications and is an efficient procedure to ameliorate motor-neuron degeneration, making it a possible therapeutic approach.

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References

  1. Vucic, S., & Kiernan, M. C. (2006). Axonal excitability properties in amyotrophic lateral sclerosis. Clinical Neurophysiology, 117, 1458–1466.

    Article  PubMed  Google Scholar 

  2. Bruijn, L. I., Miller, T. M., & Cleveland, D. W. (2004). Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annual Review of Neuroscience, 27, 723–749.

    Article  PubMed  CAS  Google Scholar 

  3. Rowland, L. P. (1998). Diagnosis of amyotrophic lateral sclerosis. Journal of Neurological Sciences, 160(Suppl 1), S6–S24.

    Article  Google Scholar 

  4. Boillee, S., Yamanaka, K., Lobsiger, C. S., et al. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science, 312, 1389–1392.

    Article  PubMed  CAS  Google Scholar 

  5. Stavarachi, M., Apostol, P., Toma, M., Cimponeriu, D., & Gavrila, L. (2010). Spinal muscular atrophy disease: a literature review for therapeutic strategies. Journal of Medicine and Life, 3, 3–9.

    PubMed  CAS  Google Scholar 

  6. Visser, J., van den Berg-Vos, R. M., Franssen, H., et al. (2007). Disease course and prognostic factors of progressive muscular atrophy. Archives of Neurology, 64, 522–528.

    Article  PubMed  Google Scholar 

  7. Lorson, C. L., Rindt, H., & Shababi, M. (2010). Spinal muscular atrophy: mechanisms and therapeutic strategies. Human Molecular Genetics, 19, R111–R118.

    Article  PubMed  CAS  Google Scholar 

  8. Silani, V., Cova, L., Corbo, M., Ciammola, A., & Polli, E. (2004). Stem-cell therapy for amyotrophic lateral sclerosis. Lancet, 364, 200–202.

    Article  PubMed  Google Scholar 

  9. Svendsen, C. N., & Langston, J. W. (2004). Stem cells for Parkinson disease and ALS: replacement or protection? Nature Medicine, 10, 224–225.

    Article  PubMed  CAS  Google Scholar 

  10. Mazzini, L., Fagioli, F., Boccaletti, R., et al. (2003). Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 4, 158–161.

    Article  PubMed  Google Scholar 

  11. Corti, S., Locatelli, F., Donadoni, C., et al. (2004). Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain, 127, 2518–2532.

    Article  PubMed  Google Scholar 

  12. Cabanes, C., Bonilla, S., Tabares, L., & Martinez, S. (2007). Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration. Neurobiology of Disease, 26, 408–418.

    Article  PubMed  CAS  Google Scholar 

  13. Kastin, A. J., Akerstrom, V., & Pan, W. (2003). Glial cell line-derived neurotrophic factor does not enter normal mouse brain. Neuroscience Letters, 340, 239–241.

    Article  PubMed  CAS  Google Scholar 

  14. Corti, S., Locatelli, F., Papadimitriou, D., Strazzer, S., & Comi, G. P. (2004). Somatic stem cell research for neural repair: current evidence and emerging perspectives. Journal of Cellular and Molecular Medicine, 8, 329–337.

    Article  PubMed  Google Scholar 

  15. Vercelli, A., Mereuta, O. M., Garbossa, D., et al. (2008). Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiology of Disease, 31, 395–405.

    Article  PubMed  CAS  Google Scholar 

  16. Blot, S., Poirier, C., & Dreyfus, P. A. (1995). The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease. Journal of Neuropathology and Experimental Neurology, 54, 812–825.

    Article  PubMed  CAS  Google Scholar 

  17. Poirier, C., Blot, S., Fernandes, M., et al. (1998). A high-resolution genetic map of mouse chromosome 19 encompassing the muscle-deficient osteochondrodystrophy (mdf-ocd) region. Mammalian Genome, 9, 390–391.

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt, W. M., Kraus, C., Hoger, H., et al. (2007). Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Reports, 8, 691–697.

    Article  PubMed  CAS  Google Scholar 

  19. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T., & Nishimune, Y. (1997). 'Green mice' as a source of ubiquitous green cells. FEBS Letters, 407, 313–319.

    Article  PubMed  CAS  Google Scholar 

  20. Sanchez, M. P., Silos-Santiago, I., Frisen, J., He, B., Lira, S. A., & Barbacid, M. (1996). Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature, 382, 70–73.

    Article  PubMed  CAS  Google Scholar 

  21. Jones, J., Jaramillo-Merchan, J., Bueno, C., Pastor, D., Viso-Leon, M., & Martinez, S. (2010). Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. Neurobiology of Disease, 40, 415–423.

    Article  PubMed  Google Scholar 

  22. McGavern, D. B., Zoecklein, L., Drescher, K. M., & Rodriguez, M. (1999). Quantitative assessment of neurologic deficits in a chronic progressive murine model of CNS demyelination. Experimental Neurology, 158, 171–181.

    Article  PubMed  CAS  Google Scholar 

  23. Kaspar, B. K., Frost, L. M., Christian, L., Umapathi, P., & Gage, F. H. (2005). Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Annals of Neurology, 57, 649–655.

    Article  PubMed  CAS  Google Scholar 

  24. Kayatekin, B. M., Gonenc, S., Acikgoz, O., Uysal, N., & Dayi, A. (2002). Effects of sprint exercise on oxidative stress in skeletal muscle and liver. European Journal of Applied Physiology, 87, 141–144.

    Article  PubMed  CAS  Google Scholar 

  25. He, Q., Wan, C., & Li, G. (2007). Concise review: multipotent mesenchymal stromal cells in blood. Stem Cells, 25, 69–77.

    Article  PubMed  CAS  Google Scholar 

  26. Herzog, E. L., Chai, L., & Krause, D. S. (2003). Plasticity of marrow-derived stem cells. Blood, 102, 3483–3493.

    Article  PubMed  CAS  Google Scholar 

  27. Giordano, A., Galderisi, U., & Marino, I. R. (2007). From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. Journal of Cellular Physiology, 211, 27–35.

    Article  PubMed  CAS  Google Scholar 

  28. Vitry, S., Bertrand, J. Y., Cumano, A., & Dubois-Dalcq, M. (2003). Primordial hematopoietic stem cells generate microglia but not myelin-forming cells in a neural environment. Journal of Neuroscience, 23, 10724–10731.

    PubMed  CAS  Google Scholar 

  29. Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J. M., et al. (2003). Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature, 425, 968–973.

    Article  PubMed  CAS  Google Scholar 

  30. Corti, S., Locatelli, F., Donadoni, C., et al. (2002). Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia. Journal of Neuroscience Research, 70, 721–733.

    Article  PubMed  CAS  Google Scholar 

  31. Javazon, E. H., Beggs, K. J., & Flake, A. W. (2004). Mesenchymal stem cells: paradoxes of passaging. Experimental Hematology, 32, 414–425.

    Article  PubMed  CAS  Google Scholar 

  32. Hall, E. D., Oostveen, J. A., & Gurney, M. E. (1998). Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia, 23, 249–256.

    Article  PubMed  CAS  Google Scholar 

  33. Howland, D. S., Liu, J., She, Y., et al. (2002). Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proceedings of the National Academy of Sciences of the United States of America, 99, 1604–1609.

    Article  PubMed  CAS  Google Scholar 

  34. Zhao, C. P., Zhang, C., Zhou, S. N., et al. (2007). Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy, 9, 414–426.

    Article  PubMed  CAS  Google Scholar 

  35. Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98, 1076–1084.

    Article  PubMed  CAS  Google Scholar 

  36. Auffray, I., Chevalier, S., Froger, J., et al. (1996). Nerve growth factor is involved in the supportive effect by bone marrow–derived stromal cells of the factor-dependent human cell line UT-7. Blood, 88, 1608–1618.

    PubMed  CAS  Google Scholar 

  37. Labouyrie, E., Dubus, P., Groppi, A., et al. (1999). Expression of neurotrophins and their receptors in human bone marrow. American Journal of Pathology, 154, 405–415.

    Article  PubMed  CAS  Google Scholar 

  38. Chen, X., Katakowski, M., Li, Y., et al. (2002). Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. Journal of Neuroscience Research, 69, 687–691.

    Article  PubMed  CAS  Google Scholar 

  39. Crigler, L., Robey, R. C., Asawachaicharn, A., Gaupp, D., & Phinney, D. G. (2006). Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Experimental Neurology, 198, 54–64.

    Article  PubMed  CAS  Google Scholar 

  40. Araki, T., & Milbrandt, J. (2000). Ninjurin2, a novel homophilic adhesion molecule, is expressed in mature sensory and enteric neurons and promotes neurite outgrowth. Journal of Neuroscience, 20, 187–195.

    PubMed  CAS  Google Scholar 

  41. Garcia, R., Aguiar, J., Alberti, E., de la Cuetara, K., & Pavon, N. (2004). Bone marrow stromal cells produce nerve growth factor and glial cell line-derived neurotrophic factors. Biochemical and Biophysical Research Communications, 316, 753–754.

    Article  PubMed  CAS  Google Scholar 

  42. Nagano, I., Shiote, M., Murakami, T., et al. (2005). Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurological Research, 27, 768–772.

    Article  PubMed  CAS  Google Scholar 

  43. Storkebaum, E., Lambrechts, D., Dewerchin, M., et al. (2005). Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neuroscience, 8, 85–92.

    Article  PubMed  CAS  Google Scholar 

  44. Wang, Y., Mao, X. O., Xie, L., et al. (2007). Vascular endothelial growth factor overexpression delays neurodegeneration and prolongs survival in amyotrophic lateral sclerosis mice. Journal of Neuroscience, 27, 304–307.

    Article  PubMed  Google Scholar 

  45. Blanquer, M., Perez Espejo, M. A., Iniesta, F., et al. (2010). Bone marrow stem cell transplantation in amyotrophic lateral sclerosis: technical aspects and preliminary results from a clinical trial. Methods and Findings in Experimental and Clinical Pharmacology, 32(Suppl A), 31–37.

    PubMed  Google Scholar 

  46. Suzuki, M., McHugh, J., Tork, C., et al. (2007). GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PloS One, 2, e689.

    Article  PubMed  Google Scholar 

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Acknowledgements

We appreciate the help of M. Rodenas, C. Redondo, O. Bahamonde, A. Torregrosa, and A. Estirado for their technical assistance. This work has been financed by EUCOMMTOOLS, Science and Innovation Ministry (MICINN BFU-2008-00588, CONSOLIDER CSD2007-00023), Valencian government (PROMETEO /2009/028), Cell Therapy Network-Carlos III Health Institute (RD06/0010/0023 and RD07/0010/2012), Alicia Koplowitz Foundation, 5P- Syndrome Foundation, and Diógenes Foundation/Elche (CATEDRA ELA).

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The authors indicate no potential conflicts of interest.

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Authors and Affiliations

  1. Sports Research Center, University Miguel Hernández, Elche, Spain

    Diego Pastor

  2. Neuroscience Institute UMH-CSIC, University Miguel Hernández, San Juan, Alicante, Spain

    Mari Carmen Viso-León, Jonathan Jones, Jesus Jaramillo-Merchán & Salvador Martínez

  3. Biomedicine Institute of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain

    Juan José Toledo-Aral

  4. Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, Hematology, BMT and Cellular therapy Unit, Crta. Madrid Cartagena, 30107, El Palmar, Murcia, Spain

    Jose M. Moraleda

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  1. Diego Pastor
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Correspondence to Salvador Martínez.

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Pastor, D., Viso-León, M.C., Jones, J. et al. Comparative Effects between Bone Marrow and Mesenchymal Stem Cell Transplantation in GDNF Expression and Motor Function Recovery in a Motorneuron Degenerative Mouse Model. Stem Cell Rev and Rep 8, 445–458 (2012). https://doi.org/10.1007/s12015-011-9295-x

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