Abstract
The growth/differentiation factor-15, GDF-15, has been found to be secreted by Schwann cells in the lesioned peripheral nervous system. To investigate whether GDF-15 plays a role in peripheral nerve regeneration, we substituted exogenous GDF-15 into 10-mm sciatic nerve gaps in adult rats and compared functional and morphological regeneration to a vehicle control group. Over a period of 11 weeks, multiple functional assessments, including evaluation of pinch reflexes, the Static Sciatic Index and of electrophysiological parameters, were performed. Regenerated nerves were then morphometrically analyzed for the number and quality of regenerated myelinated axons. Substitution of GDF-15 significantly accelerated sensory recovery while the effects on motor recovery were less strong. Although the number of regenerated myelinated axons was significantly reduced after GDF-15 treatment, the regenerated axons displayed advanced maturation corroborating the results of the functional assessments. Our results suggest that GDF-15 is involved in the complex orchestration of peripheral nerve regeneration after lesion.
Similar content being viewed by others
References
Al-Majed AA, Neumann CM, Brushart TM, Gordon T (2000) Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci 20:2602–2608
Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE (2001) Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59:901–908
Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA 94(21):11514–11519
Bosse F, Hasenpusch-Theil K, Kury P, Muller HW (2006) Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injury-dependent and reactivated developmental processes. J Neurochem 96(5):1441–1457
Bottner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C (1999a) Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1). Gene 237(1):105–111
Bottner M, Suter-Crazzolara C, Schober A, Unsicker K (1999b) Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 297(1):103–110
Boyd JG, Gordon T (2003) Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor sustain the axonal regeneration of chronically axotomized motoneurons in vivo. Exp Neurol 183(2):610–619
Bozkurt A, Tholl S, Wehner S, Tank J, Cortese M, O’Dey D, Deumens R, Lassner F, Schugner F, Groger A, Smeets R, Brook G, Pallua N (2008) Evaluation of functional nerve recovery with Visual-SSI–a novel computerized approach for the assessment of the static sciatic index (SSI). J Neurosci Methods 170:117–122
Bozkurt A, Dunda SE, Mon O’Dey D, Brook GA, Suschek CV, Pallua N (2011a) Epineurial sheath tube (EST) technique: an experimental peripheral nerve repair model. Neurol Res 33:1010–1015
Bozkurt A, Scheffel J, Brook GA, Joosten EA, Suschek CV, O’Dey DM, Pallua N, Deumens R (2011b) Aspects of static and dynamic motor function in peripheral nerve regeneration: SSI and CatWalk gait analysis. Behav Brain Res 219:55–62
Bozkurt A, Lassner F, O’Dey D, Deumens R, Bocker A, Schwendt T, Janzen C, Suschek CV, Tolba R, Kobayashi E, Sellhaus B, Tholl S, Eummelen L, Schugner F, Olde Damink L, Weis J, Brook GA, Pallua N (2012) The role of microstructured and interconnected pore channels in a collagen-based nerve guide on axonal regeneration in peripheral nerves. Biomaterials 33:1363–1375
Bunge RP (1993) Expanding roles for the Schwann cell: ensheathment, myelination, trophism and regeneration. Curr Opin Neurobiol 3:805–809
Fawcett JW, Keynes RJ (1990) Peripheral nerve regeneration. Annu Rev Neurosci 13:43–60
Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14:67–116
Geuna S, Gigo-Benato D, Rodrigues Ade C (2004) On sampling and sampling errors in histomorphometry of peripheral nerve fibers. Microsurgery 24:72–76
Haastert K, Grothe C (2007) Gene therapy in peripheral nerve reconstruction approaches. Curr Gene Ther 7:221–228
Haastert K, Lipokatic E, Fischer M, Timmer M, Grothe C (2006) Differentially promoted peripheral nerve regeneration by grafted Schwann cells over-expressing different FGF-2 isoforms. Neurobiol Dis 21:138–153
Haastert K, Ying Z, Grothe C, Gomez-Pinilla F (2008) The effects of FGF-2 gene therapy combined with voluntary exercise on axonal regeneration across peripheral nerve gaps. Neurosci Lett 443:179–183
Haastert K, Joswig H, Jaeschke KA, Samii M, Grothe C (2010) Nerve repair by end-to-side nerve coaptation: histologic and morphometric evaluation of axonal origin in a rat sciatic nerve model. Neurosurgery 66:567–576, discussion 576–567
Haastert-Talini K, Schaper-Rinkel J, Schmitte R, Bastian R, Mühlenhoff M, Schwarzer D, Draeger G, Su Y, Scheper T, Gerardy-Schahn R, Grothe C (2010) In vivo evaluation of polysialic acid as part of tissue-engineered nerve transplants. Tissue Eng Part A 16:3085–3098
Haastert-Talini K, Schmitte R, Korte N, Klode D, Ratzka A, Grothe C (2011) Electrical stimulation accelerates axonal and functional peripheral nerve regeneration across long gaps. J Neurotrauma 28:661–674
Heger J, Schiegnitz E, von Waldthausen D, Anwar MM, Piper HM, Euler G (2010) Growth differentiation factor 15 acts anti-apoptotic and pro-hypertrophic in adult cardiomyocytes. J Cell Physiol 224:120–126
Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L (1997) PLAB, a novel placental bone morphogenetic protein. Biochim Biophys Acta 1354:40–44
Huelsenbeck SC, Rohrbeck A, Handreck A, Hellmich G, Kiaei E, Roettinger I, Grothe C, Just I, Haastert-Talini K (2012) C3 Peptide promotes axonal regeneration and functional motor recovery after peripheral nerve injury. Neurotherapeutics 9:185–198
Karan D, Holzbeierlein J, Thrasher JB (2009) Macrophage inhibitory cytokine-1: possible bridge molecule of inflammation and prostate cancer. Cancer Res 69:2–5
Korte N, Schenk HC, Grothe C, Tipold A, Haastert-Talini K (2011) Evaluation of periodic electrodiagnostic measurements to monitor motor recovery after different peripheral nerve lesions in the rat. Muscle Nerve 44:63–73
Kuntzer T, van Melle G, Regli F (1997) Clinical and prognostic features in unilateral femoral neuropathies. Muscle Nerve 20(2):205–211
Lundborg G, Rosen B (2003) Nerve injury and repair—a challenge to the plastic brain. J Peripher Nerv Syst 8:209–226
Mehanna A, Mishra B, Kurschat N, Schulze C, Bian S, Loers G, Irintchev A, Schachner M (2009) Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice. Brain 132(Pt 6):1449–1462
Mimeault M, Batra SK (2010) Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer. J Cell Physiol 224:626–635
Piquilloud G, Christen T, Pfister LA, Gander B, Papaloizos MY (2007) Variations in glial cell line-derived neurotrophic factor release from biodegradable nerve conduits modify the rate of functional motor recovery after rat primary nerve repairs. Eur J Neurosci 26:1109–1117
Schindowski K, Von Bohlen Und Halbach O, Strelau J, Ridder DA, Herrmann O, Schober A, Schwaninger M, Unsicker K (2011) Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia. Cell Tissue Res 343:399–409
Schmitte R, Tipold A, Stein VM, Schenk H, Flieshardt C, Grothe C, Haastert K (2010) Genetically modified canine Schwann cells—in vitro and in vivo evaluation of their suitability for peripheral nerve tissue engineering. J Neurosci Methods 186:202–208
Schober A, Bottner M, Strelau J, Kinscherf R, Bonaterra GA, Barth M, Schilling L, Fairlie WD, Breit SN, Unsicker K (2001) Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 439:32–45
Stoll G, Jander S, Myers RR (2002) Degeneration and regeneration of the peripheral nervous system: from Augustus Waller’s observations to neuroinflammation. J Peripher Nerv Syst 7:13–27
Strelau J, Sullivan A, Bottner M, Lingor P, Falkenstein E, Suter-Crazzolara C, Galter D, Jaszai J, Krieglstein K, Unsicker K (2000) Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci 20:8597–8603
Strelau J, Schober A, Sullivan A, Schilling L, Unsicker K (2003) Growth/differentiation factor-15 (GDF-15), a novel member of the TGF-beta superfamily, promotes survival of lesioned mesencephalic dopaminergic neurons in vitro and in vivo and is induced in neurons following cortical lesioning. J Neural Transm Suppl 65:197–203
Strelau J, Strzelczyk A, Rusu P, Bendner G, Wiese S, Diella F, Altick AL, von Bartheld CS, Klein R, Sendtner M, Unsicker K (2009) Progressive postnatal motoneuron loss in mice lacking GDF-15. J Neurosci 29:13640–13648
Subramaniam S, Strelau J, Unsicker K (2003) Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem 278:8904–8912
Xu X, Li Z, Gao W (2011) Growth differentiation factor 15 in cardiovascular diseases: from bench to bedside. Biomarkers 16:466–475
Acknowledgments
This work was financially supported by the International Foundation Neurobionic (grant to K.H.T.). For excellent technical assistance, we thank Silke Fischer, Natascha Heidrich, Jennifer Metzen and Silvana Taubeler-Gerling.
Declaration of interest
Conflicts of interest are disclosed for all authors of this work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mensching, L., Börger, AK., Wang, X. et al. Local substitution of GDF-15 improves axonal and sensory recovery after peripheral nerve injury. Cell Tissue Res 350, 225–238 (2012). https://doi.org/10.1007/s00441-012-1493-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-012-1493-6