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Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats

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Abstract

Background

Axonal regeneration is a prerequisite for recovery from spinal cord injury. Here, we investigated whether Wnt3a-secreting fibroblasts exert a favorable effect on spinal cord regeneration in spinal cord-injured rats.

Methods

Spinal cord injury (SCI) was induced in rats (n = 21) using an NYU impactor. One week after SCI, rats were assigned to a Wnt3a-secreting fibroblast transplantation group (Wnt group, n = 7), a L929 fibroblast transplantation group (vehicle group, n = 7), and contusion only group (sham group, n = 7). Motor function was tested weekly for 6 weeks. Manganese-enhanced magnetic resonance imaging (ME-MRI) was performed twice, once before cell transplantation and again 5 weeks after cell transplantation. After ME-MRI, expression of the axonal regeneration marker GAP-43 was assessed by immunohistochemistry (IHC).

Results

In the Wnt group, the mean Basso–Beattie–Bresnahan score was higher than that of the vehicle and sham groups throughout the observation period. The Wnt group also exhibited stronger signal intensity on ME-MRI, and IHC revealed that GAP-43 was highly expressed in the injured spinal cord in the Wnt group.

Conclusions

These results strongly suggest that transplanted Wnt3a secreting fibroblasts promote axonal regeneration and functional improvement after SCI. Although further investigation will be necessary to clarify the intracellular mechanism by which Wnt signaling promotes axonal regeneration and functional improvement, this approach could be a highly promising therapeutic strategy for SCI.

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References

  1. Arevalo JC, Chao MV (2005) Axonal growth: where neurotrophins meet Wnts. Curr Opin Cell Biol 17:112–115

    Article  PubMed  CAS  Google Scholar 

  2. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21

    Article  PubMed  CAS  Google Scholar 

  3. Bilgen M, Dancause N, Al-Hafez B, He YY, Malone TM (2005) Manganese-enhanced MRI of rat spinal cord injury. Magn Reson Imaging 23:829–832

    Article  PubMed  CAS  Google Scholar 

  4. Blesch A, Tuszynski MH (2002) Spontaneous and neurotrophin-induced axonal plasticity after spinal cord injury. Prog Brain Res 137:415–423

    Article  PubMed  CAS  Google Scholar 

  5. Cheng H, Cao Y, Olson L (1996) Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:510–513

    Article  PubMed  CAS  Google Scholar 

  6. Dasari VR, Spomar DG, Cady C, Gujrati M, Rao JS, Dinh DH (2007) Mesenchymal stem cells from rat bone marrow downregulate Caspase-3-mediated apoptotic pathway after spinal cord injury in rats. Neurochem Res 32:2080–2093

    Article  PubMed  CAS  Google Scholar 

  7. Grill RJ, Blesch A, Tuszynski MH (1997) Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp Neurol 148:444–452

    Article  PubMed  CAS  Google Scholar 

  8. Guest JD, Hesse D, Schnell L, Schwab ME, Bunge MB, Bunge RP (1997) Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts. J Neurosci Res 50:888–905

    Article  PubMed  CAS  Google Scholar 

  9. Hofstetter CP, Schwarz EJ, Hess D (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci 99:2199–2204

    Article  PubMed  CAS  Google Scholar 

  10. Höglund CO, Frossard N (2002) Nerve growth factor and asthma. Pulm Pharmacol Ther 15:51–60

    Article  Google Scholar 

  11. Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115:3977–3978

    Article  PubMed  CAS  Google Scholar 

  12. Im J, Kim H, Kim S, Jho EH (2007) Wnt/beta-catenin signaling regulates expression of PRDC, an antagonist of the BMP-4 signaling pathway. Biochem Biophys Res Commun 354:296–301

    Article  PubMed  CAS  Google Scholar 

  13. Jeon SR, Park JH, Lee JH, Kim DY, Kim HS, Sung IY, Choi GH, Jeon MH, Kim GG (2010) Treatment of spinal cord injury with bone marrow-derived, cultured autologous mesenchymal stem cells. Tissue Eng Regen Med 7:316–322

    Google Scholar 

  14. Kalb RG, Strittmatter SM (2000) Neurobiology of spinal cord injury. Humana Press, Totowa, p xvii, 284

    Google Scholar 

  15. Kamada T, Koda M, Dezawa M, Anahara R, Toyama Y, Yoshinaga K, Hashimoto M, Koshizuka S, Nishio Y, Mannoji C, Okawa A, Yamazaki M (2010) Transplantation of human bone marrow stromal cell-derived Schwann cells reduces cystic cavity and promotes functional recovery after contusion injury of adult rat spinal cord. Neuropathology. doi:10.1111/j.1440-1789

    Google Scholar 

  16. Kishida S, Yamamoto H, Kikuchi A (2004) Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Mol Cell Biol 24:4487–4501

    Article  PubMed  CAS  Google Scholar 

  17. Lee TH (2005) Transplantation of human adipose-derived stromal cells promotes functional recovery of rat spinal cord injury. Korean J Anat 38(461):468

    Google Scholar 

  18. Liu Y, Wang X, Lu CC, Kerman R, Steward O, Xu XM, Zou Y (2008) Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J Neurosci 28:8376–8382

    Article  PubMed  CAS  Google Scholar 

  19. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810

    Article  PubMed  CAS  Google Scholar 

  20. Lu W, Yamamoto V, Ortega B, Baltimore D (2004) Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119:97–108

    Article  PubMed  CAS  Google Scholar 

  21. Miyashita T, Koda M, Kitajo K, Yamazaki M, Takahashi K, Kikuchi A, Yamashita T (2009) Wnt-Ryk signaling mediates axon growth inhibition and limits functional recovery after spinal cord injury. J Neurotrauma 26:955–964

    Article  PubMed  Google Scholar 

  22. Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4:387–398

    Article  PubMed  CAS  Google Scholar 

  23. Olgart C, Frossard N (2001) Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids. Eur Respir J 18:115–121

    Article  PubMed  CAS  Google Scholar 

  24. Roussos I, Rodríguez M, Villán D, Ariza A, Rodríguez L, García J (2005) Development of a rat model of spinal cord injury and cellular transplantation. Transplant Proc 37:4127–4130

    Article  PubMed  CAS  Google Scholar 

  25. Schnell L, Schneider R, Kolbeck R, Barde YA, Schwab ME (1994) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367:170–173

    Article  PubMed  CAS  Google Scholar 

  26. Silva AC, Lee JH, Aoki I, Koretsky AP (2004) Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations. NMR Biomed 17:532–543

    Article  PubMed  CAS  Google Scholar 

  27. Siriphorn A, Chompoopong S, Floyd C (2010) 17-Estradiol protects Schwann cells against H2O2-induced cytotoxicity and increases transplanted Schwann cell survival in a cervical hemicontusion spinal cord injury model. J Neurochem 115:864–872

    Article  PubMed  CAS  Google Scholar 

  28. Stieltjes B, Klussmann S, Bock M, Umathum R, Mangalathu J, Letellier E, Rittgen W, Edler L, Krammer PH, Kauczor HU, Martin-Villalba A, Essig M (2006) Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice. Magn Reson Med 55:1124–1131

    Article  PubMed  Google Scholar 

  29. Toledo EM, Colombres M, Inestrosa NC (2008) Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol 86:281–296

    Article  PubMed  CAS  Google Scholar 

  30. Walder N, Petter-Puchner AH, Brejnikow M, Redl H, Essig M, Stieltjes B (2008) Manganese enhanced magnetic resonance imaging in a contusion model of spinal cord injury in rats: correlation with motor function. Invest Radiol 43:277–283

    Article  PubMed  Google Scholar 

  31. Yang KH, Kim ES, Min JK, Rho SW, Rhim SC, Jeon SR (2007) Therapeutic effect and optimal injection time by human mesenchymal stem cell at spinal cord injury of rat. J Kor Neurotraumatol Soc 3:99–102

    Google Scholar 

  32. Ye JH, Houle JD (1997) Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp Neurol 143:70–81

    Article  PubMed  CAS  Google Scholar 

  33. Yin ZS, Zu B, Chang J, Zhang H (2008) Repair effect of Wnt3a protein on the contused adult rat spinal cord. Neurol Res 30:480–486

    Article  PubMed  Google Scholar 

  34. Yoshikawa S, McKinnon RD, Kokel M, Thomas JB (2003) Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422:583–588

    Article  PubMed  CAS  Google Scholar 

  35. Yun S, Rim Y, Jho EH (2007) Induced expression of the transcription of tropomodulin 1 by Wnt5a and characterization of the tropomodulin 1 promoter. Biochem Biophys Res Commun 363:727–732

    Article  PubMed  CAS  Google Scholar 

  36. Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD (2004) NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron 42:897–912

    Article  PubMed  CAS  Google Scholar 

  37. Zumbrunn J, Kinoshita K, Hyman AA, Nathke IS (2001) Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr Biol 11:44–49

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The authors thank Prof. Eek-hoon Jho in the Department of Life Science, the University of Seoul, for providing us with the cell line Mouse L929 cells and Wnt3a-secreting fibroblasts cells.

This work was supported by a Student Research Grant (09-030) from the University of Ulsan College of Medicine, Seoul, Korea, by an Asan Life Science Institute Grant (10-241) from the Asan Medical Center, Seoul, Korea, and by the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2010-0019351).

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Correspondence to Sang Ryong Jeon.

Additional information

Hyung Il Suh and Joongkee Min contributed equally to this work.

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Suh, H.I., Min, J., Choi, K.H. et al. Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats. Acta Neurochir 153, 1003–1010 (2011). https://doi.org/10.1007/s00701-011-0945-1

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  • DOI: https://doi.org/10.1007/s00701-011-0945-1

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