title: Patterns of target tissue reinnervation and trophic factor expression after nerve grafting.
abstract: BACKGROUND
  Reinnervation of target tissues determines functional outcomes after nerve grafting, which is important in traumatic injury caused by accidents or consequences resulting from surgical removal of tumors. Previous studies documented the influences of nerve repair mainly based on nerve morphometry but rarely compared the final outcomes according to target reinnervation patterns by nerve fibers of different categories.
  
  
  METHODS
  In a mouse model of nerve grafting, the authors analyzed the innervation indexes of different target tissues after transection-reimplantation on the sciatic nerve, which were defined as a parameter on the operated side normalized to that on the control side.
  
  
  RESULTS
  Muscle reinnervation appeared to be the best compared with skin reinnervation (p < 0.0001) and sweat gland reinnervation (p < 0.0001) at postoperative month 3. The sudomotor reinnervation was relatively higher than the cutaneous reinnervation (p = 0.014). The abundance of trophin transcripts for brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and neurotrophin 3 (NT3) was higher in plantar muscles on the operated side than those on the control side. In contrast, transcripts of BDNF, GDNF, nerve growth factor, and NT3 were all similar in the footpad skin between the operated and control sides.
  
  
  CONCLUSIONS
  The results suggested that, compared with the skin, muscles achieved the best reinnervation after nerve grafting, which was related to higher expression of BDNF, GDNF, and NT3 in muscles than in the skin.
authors: Taipei, Taiwan From the Departments of Anatomy and Cell Biology, the Graduate Institute of Molecular Medicine, the Graduate Institute of Brain and Mind Science, College of Medicine, School of Medicine, the Departments of Surgery and Neurology, National Taiwan University, and the Department of Surgery, Cathay General Hospital.
authors: Jung-Hsien
authors: JH
authors: Hsieh
authors: Whei-Min
authors: WM
authors: Lin
authors: Hao
authors: H
authors: Chiang
authors: Liang-Yi
authors: LY
authors: Chang
authors: Chun-Ting
authors: CT
authors: Wu
authors: Chi-Ming
authors: CM
authors: Pu
authors: June-Tai
authors: JT
authors: Wu
authors: Sung-Tsang
authors: ST
authors: Hsieh
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D009416:Nerve Regeneration / Q000502:physiology*; D020933:Neurotrophin 3 / Q000378:metabolism; D012584:Sciatic Nerve / Q000502:physiology* / Q000637:transplantation*; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery*; D011984:Sensory Receptor Cells / Q000502:physiology; D012867:Skin / Q000294:innervation / Q000378:metabolism; D013497:Sural Nerve / Q000502:physiology; D013545:Sweat Glands / Q000294:innervation / Q000378:metabolism; D013979:Tibial Nerve / Q000502:physiology; D014182:Transplantation, Autologous
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020933:Neurotrophin 3
references: Jones RH. Repair of the trigeminal nerve: A review. Aust Dent J. 2010;55:112–119
references: Mehta RP. Surgical treatment of facial paralysis. Clin Exp Otorhinolaryngol. 2009;2:1–5
references: Rovak JM, Tung TH, Mackinnon SE. The surgical management of facial nerve injury. Semin Plast Surg. 2004;18:23–30
references: Chuang DC. Adult brachial plexus reconstruction with the level of injury: Review and personal experience. Plast Reconstr Surg. 2009;124(Suppl):e359–e369
references: Guntinas-Lichius O, Straesser A, Streppel M. Quality of life after facial nerve repair. Laryngoscope. 2007;117:421–426
references: Iseli TA, Harris G, Dean NR, Iseli CE, Rosenthal EL. Outcomes of static and dynamic facial nerve repair in head and neck cancer. Laryngoscope. 2010;120:478–483
references: Allodi I, Udina E, Navarro X. Specificity of peripheral nerve regeneration: Interactions at the axon level. Prog Neurobiol. 2012;98:16–37
references: Zochodne DW. The challenges and beauty of peripheral nerve regrowth. J Peripher Nerv Syst. 2012;17:1–18
references: Verdu E, Navarro X. Comparison of immunohistochemical and functional reinnervation of skin and muscle after peripheral nerve injury. Exp Neurol. 1997;146:187–198
references: Hsieh YL, Lin WM, Lue JH, Chang MF, Hsieh ST. Effects of 4-methylcatechol on skin reinnervation: Promotion of cutaneous nerve regeneration after crush injury. J Neuropathol Exp Neurol. 2009;68:1269–1281
references: Griffin JW, Pan B, Polley MA, Hoffman PN, Farah MH. Measuring nerve regeneration in the mouse. Exp Neurol. 2010;223:60–71
references: McLachlan EM, Keast JR, Bauer M. SP- and CGRP-immunoreactive axons differ in their ability to reinnervate the skin of the rat tail. Neurosci Lett. 1994;176:147–151
references: Rajan B, Polydefkis M, Hauer P, Griffin JW, McArthur JC. Epidermal reinnervation after intracutaneous axotomy in man. J Comp Neurol. 2003;457:24–36
references: Kennedy WR, Navarro X, Kamei H. Reinnervation of sweat glands in the mouse: Axonal regeneration versus collateral sprouting. Muscle Nerve. 1988;11:603–609
references: Navarro X, Kennedy WR. Sweat gland reinnervation by sudomotor regeneration after different types of lesions and graft repairs. Exp Neurol. 1989;104:229–234
references: Koltzenburg M, Häbler HJ, Jänig W. Functional reinnervation of sweat glands in the adult cat paw by inappropriate postganglionic axons. J Auton Nerv Syst. 1996;60:193–199
references: Udina E, Cobianchi S, Allodi I, Navarro X. Effects of activity-dependent strategies on regeneration and plasticity after peripheral nerve injuries. Ann Anat. 2011;193:347–353
references: Bennett MR, McLachlan EM, Taylor RS. The formation of synapses in reinnervated mammalian striated muscle. J Physiol (Lond.). 1973;233:481–500
references: Navarro X, Verdú E, Butí M. Comparison of regenerative and reinnervating capabilities of different functional types of nerve fibers. Exp Neurol. 1994;129:217–224
references: Gorodetskaya N, Grossmann L, Constantin C, Jänig W. Functional properties of cutaneous A- and C-fibers 1-15 months after a nerve lesion. J Neurophysiol. 2009;102:3129–3141
references: Costa LM, Simões MJ, Maurício AC, Varejão AS. Chapter 7: Methods and protocols in peripheral nerve regeneration experimental research: Part IV—Kinematic gait analysis to quantify peripheral nerve regeneration in the rat. Int Rev Neurobiol. 2009;87:127–139
references: Navarro X, Vivó M, Valero-Cabré A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol. 2007;82:163–201
references: Wood MD, Kemp SW, Weber C, Borschel GH, Gordon T. Outcome measures of peripheral nerve regeneration. Ann Anat. 2011;193:321–333
references: Negredo P, Castro J, Lago N, Navarro X, Avendaño C. Differential growth of axons from sensory and motor neurons through a regenerative electrode: A stereological, retrograde tracer, and functional study in the rat. Neuroscience. 2004;128:605–615
references: Andrey I. Potentials and limitations of peripheral nerve injury models in rodents with particular reference to the femoral nerve. Ann Anat. 2011;193:276–285
references: Vilches JJ, Ceballos D, Verdú E, Navarro X. Changes in mouse sudomotor function and sweat gland innervation with ageing. Auton Neurosci. 2002;95:80–87
references: Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: A clinical-pathologic correlation. Neurology. 2009;72:1479–1486
references: Luo KR, Chao CC, Chen YT, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol. 2011;70:930–938
references: Sulaiman OA, Gordon T. Role of chronic Schwann cell denervation in poor functional recovery after nerve injuries and experimental strategies to combat it. Neurosurgery. 2009;65(Suppl):A105–A114
references: Gordon T, Chan KM, Sulaiman OA, Udina E, Amirjani N, Brushart TM. Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury. Neurosurgery. 2009;65(Suppl):A132–A144
references: Grothe C, Haastert K, Jungnickel J. Physiological function and putative therapeutic impact of the FGF-2 system in peripheral nerve regeneration: Lessons from in vivo studies in mice and rats. Brain Res Rev. 2006;51:293–299
references: Stephens HE, Belliveau AC, Gupta JS, Mirkovic S, Kablar B. The role of neurotrophins in the maintenance of the spinal cord motor neurons and the dorsal root ganglia proprioceptive sensory neurons. Int J Dev Neurosci. 2005;23:613–620
references: Gould TW, Enomoto H. Neurotrophic modulation of motor neuron development. Neuroscientist. 2009;15:105–116
references: Gordon T. The role of neurotrophic factors in nerve regeneration. Neurosurg Focus. 2009;26:E3
references: Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983;16:109–110
references: Hsieh YL, Chiang H, Tseng TJ, Hsieh ST. Enhancement of cutaneous nerve regeneration by 4-methylcatechol in resiniferatoxin-induced neuropathy. J Neuropathol Exp Neurol. 2008;67:93–104
references: Lin YY, Tseng TJ, Hsieh YL, et al. Depletion of peptidergic innervation in the gastric mucosa of streptozotocin-induced diabetic rats. Exp Neurol. 2008;213:388–396
references: Pan CL, Tseng TJ, Lin YH, Chiang MC, Lin WM, Hsieh ST. Cutaneous innervation in Guillain-Barré syndrome: Pathology and clinical correlations. Brain. 2003;126(Pt 2):386–397
references: Griffin JW, Thompson WJ. Biology and pathology of nonmyelinating Schwann cells. Glia. 2008;56:1518–1531
references: Höke A, Redett R, Hameed H, et al. Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J Neurosci. 2006;26:9646–9655
references: Gardiner NJ. Integrins and the extracellular matrix: Key mediators of development and regeneration of the sensory nervous system. Dev Neurobiol. 2011;71:1054–1072
references: Michaelevski I, Segal-Ruder Y, Rozenbaum M, et al. Signaling to transcription networks in the neuronal retrograde injury response. Sci Signal. 2010;3:ra53
references: Po MD, Calarco JA, Zhen M. Releasing the inner inhibition for axon regeneration. Neuron. 2012;73:207–209
references: El Bejjani R, Hammarlund M. Notch signaling inhibits axon regeneration. Neuron. 2012;73:268–278
references: Chen L, Wang Z, Ghosh-Roy A, et al. Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron. 2011;71:1043–1057
references: Gordon T, Sulaiman O, Boyd JG. Experimental strategies to promote functional recovery after peripheral nerve injuries. J Peripher Nerv Syst. 2003;8:236–250
references: Teng KK, Felice S, Kim T, Hempstead BL. Understanding proneurotrophin actions: Recent advances and challenges. Dev Neurobiol. 2010;70:350–359
references: Schecterson LC, Bothwell M. Neurotrophin receptors: Old friends with new partners. Dev Neurobiol. 2010;70:332–338
references: Ernsberger U. Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. Cell Tissue Res. 2009;336:349–384
references: Montaño JA, Pérez-Piñera P, García-Suárez O, Cobo J, Vega JA. Development and neuronal dependence of cutaneous sensory nerve formations: Lessons from neurotrophins. Microsc Res Tech. 2010;73:513–529
references: Gloster A, Diamond J. Sympathetic nerves in adult rats regenerate normally and restore pilomotor function during an anti-NGF treatment that prevents their collateral sprouting. J Comp Neurol. 1992;326:363–374
references: Mearow KM, Kril Y, Diamond J. Increased NGF mRNA expression in denervated rat skin. Neuroreport. 1993;4:351–354
references: Mearow KM, Kril Y, Gloster A, Diamond J. Expression of NGF receptor and GAP-43 mRNA in DRG neurons during collateral sprouting and regeneration of dorsal cutaneous nerves. J Neurobiol. 1994;25:127–142
references: Sahenk Z, Nagaraja HN, McCracken BS, et al. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 2005;65:681–689
references: Michalski B, Bain JR, Fahnestock M. Long-term changes in neurotrophic factor expression in distal nerve stump following denervation and reinnervation with motor or sensory nerve. J Neurochem. 2008;105:1244–1252
references: Geddes AJ, Angka HE, Davies KA, Kablar B. Subpopulations of motor and sensory neurons respond differently to brain-derived neurotrophic factor depending on the presence of the skeletal muscle. Dev Dyn. 2006;235:2175–2184
references: Eberhardt KA, Irintchev A, Al-Majed AA, et al. BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair. Exp Neurol. 2006;198:500–510
references: Patodia S, Raivich G. Downstream effector molecules in successful peripheral nerve regeneration. Cell Tissue Res. 2012;349:15–26
references: Bosse F. Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res. 2012;349:5–14
references: Benowitz LI, Popovich PG. Inflammation and axon regeneration. Curr Opin Neurol. 2011;24:577–583