Skip to main content

Advertisement

SpringerLink
Log in

Inducible Expression of Neurotrophic Factors by Mesenchymal Progenitor Cells Derived from Traumatically Injured Human Muscle

  • Research
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Peripheral nerve damage frequently accompanies musculoskeletal trauma and repair of these nerves could be enhanced by the targeted application of neurotrophic factors (NTFs), which are typically expressed by endogenous cells that support nerve regeneration. Injured muscle tissues express NTFs to promote reinnervation as the tissue regenerates, but the source of these factors from within the muscles is not fully understood. We have previously identified a population of mesenchymal progenitor cells (MPCs) in traumatized muscle tissue with properties that support tissue regeneration, and our hypothesis was that MPCs also secrete the NTFs that are associated with muscle tissue reinnervation. We determined that MPCs express genes associated with neurogenic function and measured the protein-level expression of specific NTFs with known functions to support nerve regeneration. We also demonstrated the effectiveness of a neurotrophic induction protocol to enhance the expression of the NTFs, which suggests that the expression of these factors may be modulated by the cellular environment. Finally, neurotrophic induction affected the expression of cell surface markers and proliferation rate of the MPCs. Our findings indicate that traumatized muscle-derived MPCs may be useful as a therapeutic cell type to enhance peripheral nerve regeneration following musculoskeletal injury.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Wiberg, M., & Terenghi, G. (2003). Will it be possible to produce peripheral nerves? Surgical Technology International, 11, 303–310.

    Google Scholar 

  2. Grant, G. A., Goodkin, R., & Kliot, M. (1999). Evaluation and surgical management of peripheral nerve problems. Neurosurgery, 44, 825–839. discussion 839–840.

    Article  CAS  Google Scholar 

  3. Sinis, N., Kraus, A., Papagiannoulis, N., Werdin, F., Schittenhelm, J., Meyermann, R., et al. (2009). Concepts and developments in peripheral nerve surgery. Clinical Neuropathology, 28, 247–262.

    CAS  Google Scholar 

  4. Campbell, W. W. (2008). Evaluation and management of peripheral nerve injury. Clinical Neurophysiology, 119, 1951–1965.

    Article  Google Scholar 

  5. Lee, S. K., & Wolfe, S. W. (2000). Peripheral nerve injury and repair. Journal of the American Academy of Orthopaedic Surgeons, 8, 243–252.

    CAS  Google Scholar 

  6. Taylor, J. S., & Bampton, E. T. (2004). Factors secreted by Schwann cells stimulate the regeneration of neonatal retinal ganglion cells. Journal of Anatomy, 204, 25–31.

    Article  CAS  Google Scholar 

  7. Tang, Y. L., Zhao, Q., Zhang, Y. C., Cheng, L., Liu, M., Shi, J., et al. (2004). Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regulatory Peptides, 117, 3–10.

    Article  CAS  Google Scholar 

  8. Nagano, M., & Suzuki, H. (2003). Quantitative analyses of expression of GDNF and neurotrophins during postnatal development in rat skeletal muscles. Neuroscience Research, 45, 391–399.

    Article  CAS  Google Scholar 

  9. Geddes, A. J., Angka, H. E., Davies, K. A., & Kablar, B. (2006). Subpopulations of motor and sensory neurons respond differently to brain-derived neurotrophic factor depending on the presence of the skeletal muscle. Developmental Dynamics, 235, 2175–2184.

    Article  CAS  Google Scholar 

  10. Meek, M. F., Den Dunnen, W. F., Schakenraad, J. M., & Robinson, P. H. (1996). Evaluation of functional nerve recovery after reconstruction with a poly (dl-lactide-epsilon-caprolactone) nerve guide, filled with modified denatured muscle tissue. Microsurgery, 17, 555–561.

    Article  CAS  Google Scholar 

  11. Hems, T. E. J., & Glasby, M. A. (1993). The limit of graft length in the experimental use of muscle grafts for nerve repair. Journal of Hand Surgery (British and European Volume), 18B, 165–170.

    Google Scholar 

  12. Meek, M. F., den Dunnen, W. F., Schakenraad, J. M., & Robinson, P. H. (1999). Evaluation of several techniques to modify denatured muscle tissue to obtain a scaffold for peripheral nerve regeneration. Biomaterials, 20, 401–408.

    Article  CAS  Google Scholar 

  13. Nesti, L. J., Jackson, W. M., Shanti, R. M., Koehler, S. M., Aragon, A. B., Bailey, J. R., et al. (2008). Differentiation potential of multipotent progenitor cells derived from war-traumatized muscle tissue. Journal of Bone and Joint Surgery (American Volume), 90, 2390–2398.

    Article  Google Scholar 

  14. Jackson, W. M., Aragon, A. B., Djouad, F., Song, Y., Koehler, S. M., Nesti, L. J., et al. (2009). Mesenchymal progenitor cells derived from traumatized human muscle. Journal of Tissue Engineering and Regenerative Medicine, 3, 129–138.

    Article  CAS  Google Scholar 

  15. Jackson, W. M., Lozito, T., Djouad, F., Kuhn, N. Z., Nesti, L. J., & Tuan, R. S. (2010). Differentiation and regeneration potential of mesenchymal progenitor cells derived from traumatized muscle tissue. Journal of Cell and Molecular Medicine. doi:10.1111/j.1582-4934.2010.01225.x.

  16. Jackson, W. M., Aragon, A. B., Bulken-Hoover, J. D., Nesti, L. J., & Tuan, R. S. (2009). Putative heterotopic ossification progenitor cells derived from traumatized muscle. Journal of Orthopaedic Research, 27, 1645–1651.

    Article  CAS  Google Scholar 

  17. Caterson, E. J., Nesti, L. J., Danielson, K. G., & Tuan, R. S. (2002). Human marrow-derived mesenchymal progenitor cells: Isolation, culture expansion, and analysis of differentiation. Molecular Biotechnology, 20, 245–256.

    Article  CAS  Google Scholar 

  18. Tondreau, T., Lagneaux, L., Dejeneffe, M., Massy, M., Mortier, C., Delforge, A., et al. (2004). Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation, 72, 319–326.

    Article  CAS  Google Scholar 

  19. Bossolasco, P., Cova, L., Calzarossa, C., Rimoldi, S. G., Borsotti, C., Deliliers, G. L., et al. (2005). Neuro-glial differentiation of human bone marrow stem cells in vitro. Experimental Neurology, 193, 312–325.

    Article  CAS  Google Scholar 

  20. Zuk, P., Zhu, M., Mizuno, H., Huang, J., Futrell, J., Katz, A., et al. (2001). Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Engineering, 7, 211–228.

    Article  CAS  Google Scholar 

  21. Greco, S. J., Zhou, C., Ye, J. H., & Rameshwar, P. (2007). An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells. Stem Cells and Development, 16, 811–826.

    Article  CAS  Google Scholar 

  22. Keilhoff, G., Stang, F., Goihl, A., Wolf, G., & Fansa, H. (2006). Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cellular and Molecular Neurobiology, 26, 1235–1252.

    Article  Google Scholar 

  23. Battula, V. L., Treml, S., Bareiss, P. M., Gieseke, F., Roelofs, H., de Zwart, P., et al. (2009). Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against cd56, cd271, and mesenchymal stem cell antigen-1. Haematologica, 94, 173–184.

    Article  CAS  Google Scholar 

  24. Wetmore, C., Cao, Y. H., Pettersson, R. F., & Olson, L. (1991). Brain-derived neurotrophic factor: Subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies. Proceedings of the National Academy of Sciences of the United States of America, 88, 9843–9847.

    Article  CAS  Google Scholar 

  25. Phinney, D. G., & Prockop, D. J. (2007). Concise review: Mesenchymal stem/multipotent stromal cells: The state of transdifferentiation and modes of tissue repair—current views. Stem Cells, 25, 2896–2902.

    Article  Google Scholar 

  26. Wislet-Gendebien, S., Leprince, P., Moonen, G., & Rogister, B. (2003). Regulation of neural markers nestin and GFAP expression by cultivated bone marrow stromal cells. Journal of Cell Science, 116, 3295–3302.

    Article  CAS  Google Scholar 

  27. Ribeiro-Resende, V. T., Pimentel-Coelho, P. M., Mesentier-Louro, L. A., Mendez, R. M., Mello-Silva, J. P., Cabral-da-Silva, M. C., et al. (2009). Trophic activity derived from bone marrow mononuclear cells increases peripheral nerve regeneration by acting on both neuronal and glial cell populations. Neuroscience, 159, 540–549.

    Article  CAS  Google Scholar 

  28. Koda, M., Kamada, T., Hashimoto, M., Murakami, M., Shirasawa, H., Sakao, S., et al. (2007). Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor to bone marrow stromal cells promotes axonal regeneration after transplantation in completely transected adult rat spinal cord. European Spine Journal, 16, 2206–2214.

    Article  Google Scholar 

  29. Fu, K. Y., Dai, L. G., Chiu, I. M., Chen, J. R., & Hsu, S. H. (2011). Sciatic nerve regeneration by microporous nerve conduits seeded with glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor gene transfected neural stem cells. Artificial Organs, 35, 363–372.

    Article  CAS  Google Scholar 

  30. Esper, R. M., & Loeb, J. A. (2004). Rapid axoglial signaling mediated by neuregulin and neurotrophic factors. Journal of Neuroscience, 24, 6218–6227.

    Article  CAS  Google Scholar 

  31. Meyer, M., Matsuoka, I., Wetmore, C., Olson, L., & Thoenen, H. (1992). Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: Different mechanisms are responsible for the regulation of bdnf and ngf mrna. Journal of Cell Biology, 119, 45–54.

    Article  CAS  Google Scholar 

  32. Funakoshi, H., Frisen, J., Barbany, G., Timmusk, T., Zachrisson, O., Verge, V. M., et al. (1993). Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. Journal of Cell Biology, 123, 455–465.

    Article  CAS  Google Scholar 

  33. Hoke, A., Redett, R., Hameed, H., Jari, R., Zhou, C., Li, Z. B., et al. (2006). Schwann cells express motor and sensory phenotypes that regulate axon regeneration. Journal of Neuroscience, 26, 9646–9655.

    Article  CAS  Google Scholar 

  34. Zhelyaznik, N., Schrage, K., McCaffery, P., & Mey, J. (2003). Activation of retinoic acid signalling after sciatic nerve injury: Up-regulation of cellular retinoid binding proteins. European Journal of Neuroscience, 18, 1033–1040.

    Article  Google Scholar 

  35. Halme, A., Cheng, M., & Hariharan, I. K. (2010). Retinoids regulate a developmental checkpoint for tissue regeneration in drosophila. Current Biology, 20, 458–463.

    Article  CAS  Google Scholar 

  36. Maden, M., & Hind, M. (2003). Retinoic acid, a regeneration-inducing molecule. Developmental Dynamics, 226, 237–244.

    Article  CAS  Google Scholar 

  37. Jackson, W. M., Nesti, L. J., & Tuan, R. S. (2010). Potential therapeutic applications of muscle-derived mesenchymal stem and progenitor cells. Expert Opinion on Biological Therapy, 10, 1–13.

    Article  Google Scholar 

  38. Keilhoff, G., Goihl, A., Stang, F., Wolf, G., & Fansa, H. (2006). Peripheral nerve tissue engineering: autologous Schwann cells vs. transdifferentiated mesenchymal stem cells. Tissue Engineering, 12, 1451–1465.

    Article  CAS  Google Scholar 

  39. Hu, J., Zhu, Q. T., Liu, X. L., Xu, Y. B., & Zhu, J. K. (2007). Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Experimental Neurology, 204, 658–666.

    Article  Google Scholar 

Download references

Acknowledgments

The study was supported in part by the NIH Intramural Research Program (Z01 AR41131 and 1ZIAAR041191), grants from the Department of Defense Military Amputee Research Program at WRAMC (PO5-A011), Comprehensive Neurosciences Program (CNP-2008-CR01) and Peer-Reviewed Orthopaedic Research Program (W81XWH-10-2-0084), and the Commonwealth of Pennsylvania Department of Health was obtained. The authors thank Dr. Paul Manner, University of Washington, for providing human skeletal tissues, James Simone, NIAMS Flow Cytometry Group, for assistance with immunotyping, and Ibardo Zambrano and Richard Booth for technical assistance.

Author information

Authors and Affiliations

  1. Cartilage Biology and Orthopaedic Branch, Department of Health and Human Services, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, 50 South Drive, Room 1525, Bethesda, MD, MSC 8022, USA

    Jamie D. Bulken-Hoover, Wesley M. Jackson, Jared A. Volger & Leon J. Nesti

  2. Clinical and Experimental Orthopaedics Laboratory, Department of Health and Human Services, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA

    Jamie D. Bulken-Hoover, Wesley M. Jackson, Youngmi Ji, Jared A. Volger & Leon J. Nesti

  3. Department of Orthopaedics and Rehabilitation, Walter Reed Army Medical Center, Washington, DC, USA

    Jamie D. Bulken-Hoover, Jared A. Volger & Leon J. Nesti

  4. Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, Department of Bioengineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 221, Pittsburgh, PA, 15219, USA

    Rocky S. Tuan

Authors
  1. Jamie D. Bulken-Hoover
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wesley M. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youngmi Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jared A. Volger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rocky S. Tuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leon J. Nesti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rocky S. Tuan or Leon J. Nesti.

Additional information

The views expressed in this manuscript are those of the authors alone and do not represent those of the United States government, the United States Army, or the Department of Defense. Nor do they represent the views of the National Institutes of Health or the Department of Health and Human Services.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bulken-Hoover, J.D., Jackson, W.M., Ji, Y. et al. Inducible Expression of Neurotrophic Factors by Mesenchymal Progenitor Cells Derived from Traumatically Injured Human Muscle. Mol Biotechnol 51, 128–136 (2012). https://doi.org/10.1007/s12033-011-9445-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-011-9445-z

Keywords

Search

Navigation