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Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

We examined whether or not peripheral nerves can be regenerated using uncultured adipose-derived regenerative cells (ADRCs). We also searched for humoral factors that might promote the proliferation or migration of Schwann cells.

Methods

Thirty rats were randomly assigned to three groups. A 10 mm sciatic nerve defect was bridged using a silicon tube filled with physiological saline (control group), type I collagen gel (collagen group), and a mixture of ADRCs and type I collagen gel (ADRC group). The regenerated tissues were studied two weeks after surgery.

Results

Continuity of regenerated tissue was observed in all rats in the control group and the ADRC group. In the collagen group, only two rats had a bridge of thin tissue, which was barely visible macroscopically. Protein gene product 9.5 staining confirmed significantly faster regeneration in the ADRC group. The distributions of the PKH-26 positive areas and the S-100 protein positive areas were different, suggesting that the transplanted cells had not differentiated into Schwann cells. In real-time RT-PCR, neuregulin-1 (Neu-1) and vascular endothelial growth factor A (VEGFA) expression were detected in uncultured ADRCs before transplantation. The regenerated tissue in the ADRC group had higher levels of Neu-1 and VEGFA expression than the control group.

Conclusions

ADRCs promote peripheral nerve regeneration. The mechanism does not involve the differentiation of transplanted cells into Schwann cells, but probably involves the secretion of some type of humoral factor such as Neu-1 or VEGFA that promotes the proliferation or migration of Schwann cells.

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References

  1. Millesi H, Meissl G, Berger A. The interfascicular nerve-grafting of the median and ulnar nerves. J Bone Joint Surg Am. 1972;54:727–50.

    PubMed  CAS  Google Scholar 

  2. Battiston B, Geuna S, Ferrero M, Tos P. Nerve repair by means of tubulization: literature review and personal clinical experience comparing biological and synthetic conduits for sensory nerve repair. Microsurgery. 2005;25:258–67.

    Article  PubMed  Google Scholar 

  3. Cordeiro PG, Seckel BR, Lipton SA, D’Amore PA, Wagner J, Madison R. Acidic fibroblast growth factor enhances peripheral nerve regeneration in vivo. Plast Reconstr Surg. 1989;83:1013–9.

    Article  PubMed  CAS  Google Scholar 

  4. Aebischer P, Salessiotis AN, Winn SR. Basic fibroblast growth factor released from synthetic guidance channels facilitates peripheral nerve regeneration across long nerve gaps. J Neurosci Res. 1989;23:282–9.

    Article  PubMed  CAS  Google Scholar 

  5. Bailey SB, Eichler ME, Villadiego A, Rich KM. The influence of fibronectin and laminin during Schwann cell migration and peripheral nerve regeneration through silicon chambers. J Neurocytol. 1993;22:176–84.

    Article  PubMed  CAS  Google Scholar 

  6. Hollowell JP, Villadiego A, Rich KM. Sciatic nerve regeneration across gaps within silicone chambers: long-term effects of NGF and consideration of axonal branching. Exp Neurol. 1990;110:45–51.

    Article  PubMed  CAS  Google Scholar 

  7. Ikeda K, Oda Y, Nakanishi I. Cultured Schwann cells transplanted between nerve gaps promote nerve regeneration. Neuro Orthopedics. 1991;11:7–16.

    Google Scholar 

  8. Cui L, Jiang J, Wei L, Zhou X, Zhou X, Fraser JL, Snider BJ, Yu SP. Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells. 2008;26:1356–65.

    Article  PubMed  CAS  Google Scholar 

  9. Kijima Y, Ishikawa M, Sunagawa T, Nakanishi K, Kamei N, Yamada K, Tanaka N, Kawamata S, Asahara T, Ochi M. Regeneration of peripheral nerve after transplantation of CD133+ cells derived from human peripheral blood. J Neurosurg. 2009;110:758–67.

    Article  PubMed  CAS  Google Scholar 

  10. Zhu M, Zhou Z, Chen Y, Schreiber R, Ransom JT, Fraser JK, Hedrick MH, Pinkernell K, Kuo HC. Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Ann Plast Surg. 2010;64:222–8.

    Article  PubMed  CAS  Google Scholar 

  11. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.

    Article  PubMed  CAS  Google Scholar 

  12. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.

    Article  PubMed  CAS  Google Scholar 

  13. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  PubMed  CAS  Google Scholar 

  14. Feng Z, Ting J, Alfonso Z, Strem BM, Fraser JK, Rutenberg J, Kuo HC, Pinkernell K. Fresh and cryopreserved, uncultured adipose tissue-derived stem and regenerative cells ameliorate ischemia-reperfusion-induced acute kidney injury. Nephrol Dial Transplant. 2010;25:3874–84.

    Article  PubMed  CAS  Google Scholar 

  15. Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, Harii K. Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg. 2007;32:48–55.

    Article  PubMed  Google Scholar 

  16. Yoshimura K, Asano Y, Aoi N, Kurita M, Oshima Y, Sato K, Inoue K, Suga H, Eto H, Kato H, Harii K. Progenitor-enriched adipose tissue transplantation as rescue for breast implant complications. Breast J. 2010;16:169–75.

    Article  PubMed  Google Scholar 

  17. Alvarez PD, García-Arranz M, Georgiev-Hristov T, Garcia-Olmo D. A new bronchoscopic treatment of tracheomediastinal fistula using autologous adipose-derived stem cells. Thorax. 2008;63:374–6.

    Article  PubMed  Google Scholar 

  18. García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–23.

    Article  PubMed  Google Scholar 

  19. Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, Ma Y. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant. 2007;11:814–7.

    Article  PubMed  CAS  Google Scholar 

  20. Fang B, Song Y, Zhao RC, Han Q, Lin Q. Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc. 2007;39:1710–3.

    Article  PubMed  CAS  Google Scholar 

  21. Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54:132–41.

    Article  PubMed  CAS  Google Scholar 

  22. Fraser JK, Zhu M, Wulur I, Alfonso Z. Adipose-derived stem cells. Methods Mol Biol. 2008;449:59–67.

    PubMed  Google Scholar 

  23. Santiago LY, Clavijo-Alvarez J, Brayfield C, Rubin JP, Marra KG. Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant. 2009;18:145–58.

    Article  PubMed  Google Scholar 

  24. di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, Kalbermatten DF. Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg. 2010;63:1544–52.

    Article  PubMed  Google Scholar 

  25. Erba P, Mantovani C, Kalbermatten DF, Pierer G, Terenghi G, Kingham PJ. Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. J Plast Reconstr Aesthet Surg. 2010;63:e811–7.

    Article  PubMed  CAS  Google Scholar 

  26. Garratt AN, Britsch S, Birchmeier C. Neuregulin, a factor with many functions in the life of a Schwann cell. Bioassays. 2000;22:987–96.

    Article  CAS  Google Scholar 

  27. Ogata T, Yamamoto S, Nakamura K, Tanaka S. Signaling axis in Schwann cell proliferation and differentiation. Mol Neurobiol. 2006;33:51–62.

    Article  PubMed  CAS  Google Scholar 

  28. Rosenstein JM, Krum JM, Ruhrberg C. VEGF in the nervous system. Organogenesis. 2010;6:107–14.

    Article  PubMed  Google Scholar 

  29. Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res. 1999;846:219–28.

    Article  PubMed  CAS  Google Scholar 

  30. Hobson MI, Green CJ, Terenghi G. VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat. 2000;197:591–605.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mr. Toshiya Nomura and Ms. Yoko Kasai for their skillful technical assistance.

Conflict of interest

None of the authors have any conflicts of interest or disclosures in relation to this work.

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Correspondence to Kaoru Tada.

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Suganuma, S., Tada, K., Hayashi, K. et al. Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration. J Orthop Sci 18, 145–151 (2013). https://doi.org/10.1007/s00776-012-0306-9

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  • DOI: https://doi.org/10.1007/s00776-012-0306-9

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