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Human adipose-derived stem cells stimulate neuroregeneration

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Abstract

Traumatic brain injuries and degenerative neurological disorders such as Alzheimer’s dementia, Parkinson’s disease, amyotrophic lateral sclerosis and many others are characterized by loss of brain cells and supporting structures. Restoring microanatomy and function using stem cells is a promising therapeutic approach. Among the many various sources, adipose-derived stem cells (ADSCs) are one of the most easily harvested alternatives, they multiply rapidly, and they demonstrate low immunogenicity with an ability to differentiate into several cell types. The objective of this study was to evaluate the effect of xenotransplanted human ADSCs on post-traumatic regeneration of rat sciatic nerve. Peripheral reconstruction following complete sciatic transection and autonerve grafting was complemented by intra-operative injection of hADSCs into the proximal and distal stumps. The injury caused gliosis and apoptosis of sensory neurons in the lumbar 5 (L5) ganglia in the control rodents; however, animals treated with hADSCs demonstrated a smaller amount of cellular loss. Formation of amputation neuroma, which hinders axonal repair, was less prominent in the experimental group, and immunohistochemical analysis of myelin basic protein showed good myelination 65 days after surgery. At this point, control groups still exhibited high levels of microglia/macrophage-specific marker Iba-1 and proliferating cell nuclear antigen, the mark of an ongoing inflammation and incomplete axonal growth 2 months after the injury. This report demonstrates that hADSCs promote neuronal survival in the spinal ganglion, fuel axonal repair and stimulate the regeneration of peripheral nerves.

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References

  1. Dubovy P. Schwann cells and endoneurial extracellular matrix molecules as potential cues for sorting of regenerated axons: a review. Anat Sci Int. 2004;79(4):198–208. doi:10.1111/j.1447-073x.2004.00090.x.

    Article  CAS  PubMed  Google Scholar 

  2. Dezawa M, Ishikawa H, Hoshino M, Itokazu Y, Nabeshima Y. Potential of bone marrow stromal cells in applications for neuro-degenerative, neuro-traumatic and muscle degenerative diseases. Curr Neuropharmacol. 2005;3(4):257–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Radtke C, Wewetzer K, Reimers K, Vogt PM. Transplantation of olfactory ensheathing cells as adjunct cell therapy for peripheral nerve injury. Cell Transplant. 2011;20(2):145–52. doi:10.3727/096368910X522081.

    Article  PubMed  Google Scholar 

  4. Kingham PJ, Kalbermatten DF, Mahay D, Armstrong SJ, Wiberg M, Terenghi G. Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol. 2007;207(2):267–74. doi:10.1016/j.expneurol.2007.06.029.

    Article  CAS  PubMed  Google Scholar 

  5. Arkhipova SS, Raginov IS, Mukhitov AR, Chelyshev YA. Satellite cells of sensory neurons after various types of sciatic nerve trauma in the rat. Neurosci Behav Physiol. 2010;40(6):609–14. doi:10.1007/s11055-010-9303-7.

    Article  CAS  PubMed  Google Scholar 

  6. Gordon T, Tyreman N, Raji MA. The basis for diminished functional recovery after delayed peripheral nerve repair. J Neurosci. 2011;31(14):5325–34. doi:10.1523/JNEUROSCI.6156-10.2011.

    Article  CAS  PubMed  Google Scholar 

  7. McKay Hart A, Brannstrom T, Wiberg M, Terenghi G. Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death and elimination. Exp Brain Res. 2002;142(3):308–18. doi:10.1007/s00221-001-0929-0.

    Article  PubMed  Google Scholar 

  8. Raginov IS, Chelyshev IuA. Post-traumatic survival in different subpopulations of sensory neurons. Morfologiia. 2003;124(4):47–50.

    CAS  PubMed  Google Scholar 

  9. Tandrup T, Woolf CJ, Coggeshall RE. Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol. 2000;422(2):172–80. doi:10.1002/(SICI)1096-9861(20000626)422:2<172:AID-CNE2>3.0.CO.

    Article  CAS  PubMed  Google Scholar 

  10. Vigneswara V, Berry M, Logan A, Ahmed Z. Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from apoptosis after serum withdrawal. PLoS One. 2013;8(2):e57861. doi:10.1371/journal.pone.0057861.PONE-D-12-35011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weerasuriya A, Mizisin AP. The blood-nerve barrier: structure and functional significance. Methods Mol Biol. 2011;686:149–73. doi:10.1007/978-1-60761-938-3_6.

    Article  CAS  PubMed  Google Scholar 

  12. Tamaki T, Hirata M, Soeda S, Nakajima N, Saito K, Nakazato K, et al. Preferential and comprehensive reconstitution of severely damaged sciatic nerve using murine skeletal muscle-derived multipotent stem cells. PLoS One. 2014;9(3):e91257. doi:10.1371/journal.pone.0091257.PONE-D-13-38421.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35(5):601–12. doi:10.1007/s00281-013-0382-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kalinina NI, Sysoeva VY, Rubina KA, Parfenova YV, Tkachuk VA. Mesenchymal stem cells in tissue growth and repair. Acta Naturae. 2011;3(4):30–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Faroni A, Terenghi G, Reid AJ. Adipose-derived stem cells and nerve regeneration: promises and pitfalls. Int Rev Neurobiol. 2013;108:121–36. doi:10.1016/B978-0-12-410499-0.00005-8.

    Article  CAS  PubMed  Google Scholar 

  16. Solovyeva VV, Salafutdinov II, Martynove EV. Human adipose derived stem cells do not alter cytokine secretion in response to the genetic modification with pEGFP-N2 Plasmid DNA. World Appl Sci J. 2013;26(7):968–72.

    CAS  Google Scholar 

  17. Momeni HR, Soleimani Mehranjani M, Shariatzadeh MA, Haddadi M. Caspase-mediated apoptosis in sensory neurons of cultured dorsal root ganglia in adult mouse. Cell J. 2013;15(3):212–7.

    PubMed  PubMed Central  Google Scholar 

  18. Chen L, Qiu R, Xu Q. Mesenchymal stem cell therapy for neurodegenerative diseases. J Nanosci Nanotechnol. 2014;14(1):969–75.

    Article  CAS  PubMed  Google Scholar 

  19. Masgutov RF, Salafutdinov II, Bogov AA. The stimulation of posttraumatic regeneration of the sciatic nerve of a rat with a plasmid expressing a vascular endothelial growth factor and the basic fibroblast growth factor. Cell Transplant Tissue Eng. 2011;6(3):67–70.

    Google Scholar 

  20. Cheutin T, Gorski SA, May KM, Singh PB, Misteli T. In vivo dynamics of Swi6 in yeast: evidence for a stochastic model of heterochromatin. Mol Cell Biol. 2004;24(8):3157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lo DC. Neurotrophic factors and synaptic plasticity. Neuron. 1995;15(5):979–81.

    Article  CAS  PubMed  Google Scholar 

  22. Goldberg JL, Barres BA. Nogo in nerve regeneration. Nature. 2000;403(6768):369–70. doi:10.1038/35000309.

    Article  CAS  PubMed  Google Scholar 

  23. Ribeiro-Resende VT, Carrier-Ruiz A, Lemes RM, Reis RA, Mendez-Otero R. Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system. Mol Neurodegener. 2012;7:34. doi:10.1186/1750-1326-7-34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Otoshi K, Kikuchi S, Konno S, Sekiguchi M. The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain-related behavior after application of nucleus pulposus onto the nerve root in rats. Spine (Phila Pa 1976). 2010;35(3):264–71. doi:10.1097/BRS.0b013e3181b8b04f.

    Article  Google Scholar 

  25. Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 1999;13(24):3179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cheng C, Zochodne DW. Sensory neurons with activated caspase-3 survive long-term experimental diabetes. Diabetes. 2003;52(9):2363–71.

    Article  CAS  PubMed  Google Scholar 

  27. Wood MD, Kemp SW, Weber C, Borschel GH, Gordon T. Outcome measures of peripheral nerve regeneration. Ann Anat. 2011;193(4):321–33. doi:10.1016/j.aanat.2011.04.008.

    Article  PubMed  Google Scholar 

  28. Abram SE, Yi J, Fuchs A, Hogan QH. Permeability of injured and intact peripheral nerves and dorsal root ganglia. Anesthesiology. 2006;105(1):146–53.

    Article  PubMed  Google Scholar 

  29. Berg A, Zelano J, Pekna M, Wilhelmsson U, Pekny M, Cullheim S. Axonal regeneration after sciatic nerve lesion is delayed but complete in GFAP- and vimentin-deficient mice. PLoS One. 2013;8(11):e79395. doi:10.1371/journal.pone.0079395.PONE-D-13-32448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45. doi:10.3389/fncel.2013.00045.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91(2):461–553. doi:10.1152/physrev.00011.2010.

    Article  CAS  PubMed  Google Scholar 

  32. Shachpazyan NR, Astrelina TA, Yakovleva MV. Mesenchymal stem cells derived from various human tissues: biological properties, evaluation of their quality and safety for clinical use. Cell Transplant Tissue Eng. 2012;7(1):23–33.

    Google Scholar 

  33. Reid AJ, Sun M, Wiberg M, Downes S, Terenghi G, Kingham PJ. Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience. 2011;199:515–22. doi:10.1016/j.neuroscience.2011.09.064.

    Article  CAS  PubMed  Google Scholar 

  34. Marconi S, Castiglione G, Turano E, Bissolotti G, Angiari S, Farinazzo A, et al. Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Part A. 2012;18(11–12):1264–72. doi:10.1089/ten.TEA.2011.0491.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study was supported by Grant 13-04-12035 from Russian Foundation for Basic Research. This work was performed in accordance with Program of Competitive Growth of Kazan Federal University and subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities. Yana O. Mukhamedshina was supported by Presidential grant for government support of young scientists (PhD) from the Russian Federation (4020.2015.7). Some of the experiments were conducted using equipment at the Interdisciplinary center for collective use of Kazan Federal University supported by Ministry of Education of Russia (ID RFMEFI59414X0003), Interdisciplinary center for analytical microscopy, and Pharmaceutical Research and Education Center, Kazan (Volga Region) Federal University, Kazan, Russia. The authors are also indebted to Drs. Gallyamov and Bogov for their assistance in animal handling.

Conflict of interest

Authors declare no conflict of interest.

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Authors and Affiliations

  1. Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia

    Ruslan F. Masgutov, Galina A. Masgutova, Margarita N. Zhuravleva, Ilnur I. Salafutdinov, Regina T. Mukhametshina, Yana O. Mukhamedshina, Andrey P. Kiyasov, András Palotás & Albert A. Rizvanov

  2. Republic Clinical Hospital, Kazan, Russia

    Ruslan F. Masgutov & Ilnur I. Salafutdinov

  3. Universidade Federal de Viçosa, Viçosa, Brazil

    Luciana M. Lima

  4. Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Helton J. Reis

  5. Asklepios-Med (private medical practice and research center), Kossuth Lajos sgt. 23, Szeged, 6722, Hungary

    András Palotás

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  1. Ruslan F. Masgutov
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  2. Galina A. Masgutova
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  3. Margarita N. Zhuravleva
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  4. Ilnur I. Salafutdinov
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  5. Regina T. Mukhametshina
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  6. Yana O. Mukhamedshina
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  7. Luciana M. Lima
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  8. Helton J. Reis
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  9. Andrey P. Kiyasov
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  11. Albert A. Rizvanov
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Corresponding authors

Correspondence to András Palotás or Albert A. Rizvanov.

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Masgutov, R.F., Masgutova, G.A., Zhuravleva, M.N. et al. Human adipose-derived stem cells stimulate neuroregeneration. Clin Exp Med 16, 451–461 (2016). https://doi.org/10.1007/s10238-015-0364-3

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  • DOI: https://doi.org/10.1007/s10238-015-0364-3

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