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Acta Neurochirurgica

Published in:

01-05-2011 | Experimental research

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

Authors: Hyung Il Suh, Joongkee Min, Kyung Hyo Choi, Seong Who Kim, Ki Soo Kim, Sang Ryong Jeon

Published in: Acta Neurochirurgica | Issue 5/2011

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.

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

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

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

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

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

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 32:2080–2093PubMedCrossRef

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 148:444–452PubMedCrossRef

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 50:888–905PubMedCrossRef

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 99:2199–2204PubMedCrossRef

10.

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

11.

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

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 354:296–301PubMedCrossRef

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

14.

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

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

16.

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

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

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 28:8376–8382PubMedCrossRef

19.

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

20.

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

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 26:955–964PubMedCrossRef

22.

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

23.

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

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 37:4127–4130PubMedCrossRef

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 367:170–173PubMedCrossRef

26.

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

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 115:864–872PubMedCrossRef

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 55:1124–1131PubMedCrossRef

29.

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

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 43:277–283PubMedCrossRef

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

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 143:70–81PubMedCrossRef

33.

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

34.

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

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 363:727–732PubMedCrossRef

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 42:897–912PubMedCrossRef

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 11:44–49PubMedCrossRef

Title: Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats
Authors: Hyung Il Suh
Joongkee Min
Kyung Hyo Choi
Seong Who Kim
Ki Soo Kim
Sang Ryong Jeon
Publication date: 01-05-2011
Publisher: Springer Vienna
Published in: Acta Neurochirurgica / Issue 5/2011
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-011-0945-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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