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Transplanted Modified Muscle Progenitor Cells Expressing a Mixture of Neurotrophic Factors Delay Disease Onset and Enhance Survival in the SOD1 Mouse Model of ALS

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Abstract

Neurotrophic factors (NTFs) are essential growth factor proteins that support the development, survival, and proper function of neurons. We have developed muscle progenitor cell (MPC) populations expressing brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), or insulin-like growth factor-1 (IGF-1). Transplantation of a mixture of such MPC populations (MPC-MIX) into the hind legs of SOD1 G93A transgenic mice (SOD1 mice), the commonly used model of ALS, delayed the onset of disease symptoms by 30 days and prolonged the average lifespan by 13 days. Treated mice also showed a decrease in the degeneration of neuromuscular junction and an increase in axonal survival. Cellular mechanism assays suggest a synergistic rescue effect of NTFs that involves the AKT and BAD signaling pathways. The results suggest that long-term delivery of a mixture of several NTFs by the transplantation of engineered MPC has a beneficial effect in the ALS mouse model.

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Acknowledgments

The study was supported by the Muscular Diseases Association (MDA), USA (D.O.) and ISF Legacy Heritage Biomedical Fund 561/11 (E.P.).

Conflict of Interest

D. Offen is consultant in BrainStorm Cell Therapeutics, Israel. The other authors declare no conflict of interest.

Author Contributions

M.N., D.Y., E.P., and D.O. conceived the study, performed the experiments, analyzed the data, and prepared the manuscript. K.B, Y. B., and T.B provided technical support. D.O. and E.P. provided financial support.

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Authors and Affiliations

  1. Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    M. Dadon-Nachum, T. Ben-Zur, Y. Barhum & D. Offen

  2. Dept of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    K. Ben-Yaacov & E. Perlson

  3. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    D. Yaffe

  4. Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel, 49100

    D. Offen

Authors
  1. M. Dadon-Nachum
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  2. K. Ben-Yaacov
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  3. T. Ben-Zur
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  4. Y. Barhum
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  5. D. Yaffe
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  6. E. Perlson
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  7. D. Offen
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Correspondence to D. Offen.

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Dadon-Nachum, M., Ben-Yaacov, K., Ben-Zur, T. et al. Transplanted Modified Muscle Progenitor Cells Expressing a Mixture of Neurotrophic Factors Delay Disease Onset and Enhance Survival in the SOD1 Mouse Model of ALS. J Mol Neurosci 55, 788–797 (2015). https://doi.org/10.1007/s12031-014-0426-0

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  • DOI: https://doi.org/10.1007/s12031-014-0426-0

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