Skip to main content
SpringerLink
Log in

Transplantation of Human Adipose Mesenchymal Stem Cells in Non-Immunosuppressed GRMD Dogs is a Safe Procedure

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

The possibility to treat Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, through cell therapy with mesenchymal stromal cells (MSCs) has been widely investigated in different animal models. However, some crucial questions need to be addressed before starting human therapeutic trials, particularly regarding its use for genetic disorders. How safe is the procedure? Are there any side effects following mesenchymal stem cell transplantation? To address these questions for DMD the best model is the golden retriever muscular dystrophy dog (GRMD), which is the closest model to the human condition displaying a much longer lifespan than other models. Here we report the follow-up of 5 GRMD dogs, which were repeatedly transplanted with human adipose-derived mesenchymal stromal cells (hASC), derived from different donors. Xenogeneic cell transplantation, which was done without immunosuppression, was well tolerated in all animals with no apparent long-term adverse effect. In the present study, we show that repeated heterologous stem-cell injection is a safe procedure, which is fundamental before starting human clinical trials.

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

Similar content being viewed by others

References

  1. Wicklund, M. P. (2013). The muscular dystrophies. continuum (Minneapolis Minnesota), 19, 1535–1570.

    Google Scholar 

  2. Emery, A. E. H. (2002). The muscular dystrophies. Lancet, 359, 687–695.

    Article  CAS  PubMed  Google Scholar 

  3. Vainzof, M., et al. (2008). Animal models for genetic neuromuscular diseases. Journal of Molecular Neuroscience, 34, 241–248.

    Article  CAS  PubMed  Google Scholar 

  4. Allamand, V., & Campbell, K. P. (2000). Animal models for muscular dystrophy: valuable tools for the development of therapies. Human Molecular Genetics, 9, 2459–2467.

    Article  CAS  PubMed  Google Scholar 

  5. Sharp, N. J., et al. (1992). An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics, 13, 115–121.

    Article  CAS  PubMed  Google Scholar 

  6. Zatz, M., et al. (2014). Milder course in Duchenne patients with nonsense mutations and no muscle dystrophin. Neuromuscular Disorders, 24, 986–989.

    Article  CAS  PubMed  Google Scholar 

  7. Zucconi, E., et al. (2010). Ringo: discordance between the molecular and clinical manifestation in a golden retriever muscular dystrophy dog. Neuromuscular Disorders, 20, 64–70.

    Article  PubMed  Google Scholar 

  8. Zatz, M., et al. (2015). A normal life without muscle dystrophin. Neuromuscular Disorders. doi:10.1016/j.nmd.2015.02.007.

    Google Scholar 

  9. Vieira, N. M., et al. (2015). Muscular dystrophy in a family of labrador retrievers with no muscle dystrophin and a mild phenotype. Neuromuscular Disorders. doi:10.1016/j.nmd.2015.02.012.

    Google Scholar 

  10. Quattrocelli, M., Cassano, M., Crippa, S., Perini, I., & Sampaolesi, M. (2010). Cell therapy strategies and improvements for muscular dystrophy. Cell Death and Differentiation, 17, 1222–1229.

    Article  CAS  PubMed  Google Scholar 

  11. Sampaolesi, M., et al. (2006). Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature, 444, 574–579.

    Article  CAS  PubMed  Google Scholar 

  12. Nitahara-Kasahara, Y., et al. (2012). Long-term engraftment of multipotent mesenchymal stromal cells that differentiate to form myogenic cells in dogs with Duchenne muscular dystrophy. Molecular Therapy, 20, 168–177.

    Article  CAS  PubMed  Google Scholar 

  13. Rouger, K., et al. (2011). Systemic delivery of allogenic muscle stem cells induces long-term muscle repair and clinical efficacy in duchenne muscular dystrophy dogs. The American Journal of Pathology, 179, 2501–2518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cerletti, M., et al. (2008). Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles. Cell, 134, 37–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Valadares, M. C., et al. (2014). Human adipose tissue derived pericytes increase life span in Utrn (tm1Ked) Dmd (mdx) /J mice. Stem Cell Reviews, 10, 830–840.

    Article  CAS  PubMed  Google Scholar 

  16. Vieira, N. M., et al. (2012). Human adipose-derived mesenchymal stromal cells injected systemically into GRMD dogs without immunosuppression are able to reach the host muscle and express human dystrophin. Cell Transplantation, 21, 1407–1417.

    Article  CAS  PubMed  Google Scholar 

  17. Honeyman, K., Carville, K. S., Howell, J. M., Fletcher, S., & Wilton, S. D. (1999). Development of a snapback method of single-strand conformation polymorphism analysis for genotyping Golden Retrievers for the X-linked muscular dystrophy allele. American Journal of Veterinary Research, 60, 734–737.

    CAS  PubMed  Google Scholar 

  18. Vieira, N. M., et al. (2008). SJL dystrophic mice express a significant amount of human muscle proteins following systemic delivery of human adipose-derived stromal cells without immunosuppression. Stem Cells, 26, 2391–2398.

    Article  PubMed  Google Scholar 

  19. Zuk, P. A., et al. (2002). Human adipose tissue is a source of multipotent stem cells. Molecular Biology of the Cell, 13, 4279–4295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Caplan, A. I. (1991). Mesenchymal stem cells. Journal of Orthopaedic Research, 9, 641–650.

    Article  CAS  PubMed  Google Scholar 

  21. Dominici, M., et al. (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 

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

    Article  CAS  PubMed  Google Scholar 

  23. Singer, N. G., & Caplan, A. I. (2011). Mesenchymal stem cells: mechanisms of inflammation. Annual Review of Pathology, 6, 457–478.

    Article  CAS  PubMed  Google Scholar 

  24. Caplan, A. I., & Sorrell, J. M. (2015). The MSC curtain that stops the immune system. Immunology Letters. doi:10.1016/j.imlet.2015.06.005.

    PubMed  Google Scholar 

  25. Ichim, T. E., et al. (2010). Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy. Cellular Immunology, 260, 75–82.

    Article  CAS  PubMed  Google Scholar 

  26. Le Blanc, K. (2006). Mesenchymal stromal cells: tissue repair and immune modulation. Cytotherapy, 8, 559–561.

    Article  PubMed  Google Scholar 

  27. Le Blanc, K., Tammik, L., Sundberg, B., Haynesworth, S. E., & Ringdén, O. (2003). Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scandinavian Journal of Immunology, 57, 11–20.

    Article  PubMed  Google Scholar 

  28. English, K. (2013). Mechanisms of mesenchymal stromal cell immunomodulation. Immunology and Cell Biology, 91, 19–26.

    Article  CAS  PubMed  Google Scholar 

  29. N. M. Vieira et al. (2015) Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. Cell, 1–10.

  30. B. Gharaibeh, M. Lavasani, J. H. Cummins, J. Huard. (2011). Terminal differentiation is not a major determinant for the success of stem cell therapy - cross-talk between muscle-derived stem cells and host cells. Stem Cell Research & Therapy.

  31. Pinheiro, C. H. D. J., et al. (2012). Local injections of adipose-derived mesenchymal stem cells modulate inflammation and increase angiogenesis ameliorating the dystrophic phenotype in dystrophin-deficient skeletal muscle. Stem Cell Reviews, 8, 363–374.

    Article  PubMed  Google Scholar 

  32. Murphy, M. B., Moncivais, K., & Caplan, A. I. (2013). Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Experimental and Molecular Medicine, 45, e54.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lee, S.-R., et al. (2015). Long-term survival and differentiation of human neural stem cells in nonhuman primate brain with no immunosuppression. Cell Transplantation, 24, 191–201.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The collaboration of the following persons is gratefully acknowledged: Mariane Secco, Eder Zucconi, Mariz Vainzof, Tatiana Jazedje, Oswaldo Keith Okamoto, Carolina G. Pires, Daniel Sanches, Marta Canovas, Munira Tanezi Guilhon e Sá, Constância Gotto, Vanessa Sato, Wagner Falciano, and all the Genocão team. This work was supported by CEPID/FAPESP, INCT, CNPq, ABDIM, AACD, the FID project and the Duchenne Research fund.

Author information

Authors and Affiliations

  1. Human Genome and Stem-cell Research Center, Institute of Biosciences, University of São Paulo, Rua do Matão, n.106 - Cidade Universitária, São Paulo, SP, Brasil, 05508-090

    M. V. Pelatti, J. P. A. Gomes, N. M. S. Vieira, E. Cangussu, V. Landini, T. Andrade, M. Sartori, L. Petrus & Mayana Zatz

Authors
  1. M. V. Pelatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. P. A. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. M. S. Vieira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Cangussu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. Landini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Sartori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Petrus
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mayana Zatz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mayana Zatz.

Ethics declarations

Conflict of Interest

The authors indicate no potential conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary figure 1

Smart Ultrasound evaluation 3 months after treatment. (PDF 516 kb)

Supplementary figure 2

Tutu Ultrasound evaluation 3 months after treatment. (PDF 554 kb)

Supplementary figure 3

Smart x-ray evaluation 3 months after treatment. (DOCX 1044 kb)

Supplementary figure 4

Tutu x-ray evaluation 3 months after treatment. (DOCX 1038 kb)

Supplementary figure 5

Yuan Ultrasound evaluation 61/2 years after treatment. (PDF 504 kb)

Supplementary figure 6

Yuan x-ray evaluation 61/2 years after treatment. (DOCX 866 kb)

Supplementary figure 7

Rum Ultrasound evaluation 1 year after treatment. (PDF 526 kb)

Supplementary figure 8

Rum x-ray evaluation. (DOCX 1220 kb)

Supplementary table 1

Cardiac evaluations of Sushi (normal dog), Smart and Tutu before and after treatment. Cardiac data include electrocardiography, mean arterial pressure and echocardiography. (PDF 441 kb)

Supplementary table 2

Complete blood test, including blood count and biochemical blood test of Sushi (normal dog), Smart and Tutu. Blood was collected before and 48 h after each stem cell injection. Presented data show minimum and maximum values observed in all 18 blood tests. (PDF 290 kb)

Supplementary table 3

Last complete blood test of Sushi (normal dog), Smart, Tutu, Yuan and Rum. Evaluation was performed 6 month after Tutu and Smart treatment; 10 months after Rum treatment; and 61/2year after Yuan treatment. (PDF 200 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pelatti, M.V., Gomes, J.P.A., Vieira, N.M.S. et al. Transplantation of Human Adipose Mesenchymal Stem Cells in Non-Immunosuppressed GRMD Dogs is a Safe Procedure. Stem Cell Rev and Rep 12, 448–453 (2016). https://doi.org/10.1007/s12015-016-9659-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-016-9659-3

Keywords

Search

Navigation