Peripheral nerve grafts promoting central nervous system regeneration after spinal cord injury in the primate

Restricted access

Spine - 1 year subscription bundle (Individuals Only)

USD  $369.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Object. Partial restoration of hindlimb function in adult rats following spinal cord injury (SCI) has been demonstrated using a variety of transplantation techniques. The purpose of the present study was twofold: 1) to determine whether strategies designed to promote regeneration in the rat can yield similar results in the primate; and 2) to establish whether central nervous system (CNS) regeneration will influence voluntary grasping and locomotor function in the nonhuman primate.

Methods. Ten cynomologus monkeys underwent T-11 laminectomy and resection of a 1-cm length of hemispinal cord. Five monkeys received six intercostal nerve autografts and fibrin glue containing acidic fibroblast growth factor (2.1 µg/ml) whereas controls underwent the identical laminectomy procedure but did not receive the nerve grafts. At 4 months postgrafting, the spinal cord—graft site was sectioned and immunostained for peripheral myelin proteins, biotinylated dextran amine, and tyrosine hydroxylase, whereas the midpoint of the graft was analyzed histologically for the total number of myelinated axons within and around the grafts. The animals underwent pre- and postoperative testing for changes in voluntary hindlimb grasping and gait.

Conclusions. 1) A reproducible model of SCI in the primate was developed. 2) Spontaneous recovery of the ipsilateral hindlimb function occurred in both graft- and nongraft—treated monkeys over time without evidence of recovering the ability for voluntary tasks. 3) Regeneration of the CNS from proximal spinal axons into the peripheral nerve grafts was observed; however, the grafts did not promote regeneration beyond the lesion site. 4) The grafts significantly enhanced (p < 0.0001) the regeneration of myelinated axons into the region of the hemisected spinal cord compared with the nongrafted animals.

Article Information

Contributor Notes

Address reprint requests to: Allan D. O. Levi, M.D., Ph.D., The Miami Project to Cure Paralysis, University of Miami School of Medicine, Lois Pope LIFE Center, 1095 NW 14th Terrace, Miami, Florida 33136. email: alevi@med.miami.edu.
Headings
References
  • 1.

    Aoki MFujito YKosaka Iet al: Does collateral sprouting from corticospinal fibers participate in motor recovery after spinal hemisection in monkeys? in Flohr H (ed): Post-Lesion Neural Plasticity. New York: Springer-Verlag1988 pp.223231Aoki M Fujito Y Kosaka I et al: Does collateral sprouting from corticospinal fibers participate in motor recovery after spinal hemisection in monkeys? in Flohr H (ed): Post-Lesion Neural Plasticity. New York: Springer-Verlag 1988 pp. 223–231

    • Search Google Scholar
    • Export Citation
  • 2.

    Aoki MFujito YMizuguchi Aet al: Recovery of hindlimb movement after spinal hemisection and collateral sprouting from corticospinal fibers in monkeys in ShimamvraHGrillner SEdgerton VR (eds): Neurobiological Basis of Human Locomotion. Tokyo: Japan Scientific Societies Press1991 pp 401404Aoki M Fujito Y Mizuguchi A et al: Recovery of hindlimb movement after spinal hemisection and collateral sprouting from corticospinal fibers in monkeys in Shimamvra H Grillner S Edgerton VR (eds): Neurobiological Basis of Human Locomotion. Tokyo: Japan Scientific Societies Press 1991 pp 401–404

    • Search Google Scholar
    • Export Citation
  • 3.

    Azulay ASchwartz AS: The role of the dorsal funiculus of the primate in tactile discrimination. Exp Neurology 46:3153321975Azulay A Schwartz AS: The role of the dorsal funiculus of the primate in tactile discrimination. Exp Neurology 46:315–332 1975

    • Search Google Scholar
    • Export Citation
  • 4.

    Basso DMBeattie MSBresnahan JC: A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1211995Basso DM Beattie MS Bresnahan JC: A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21 1995

    • Search Google Scholar
    • Export Citation
  • 5.

    Bernstein-Goral HBregman BS: Spinal cord transplants support the regeneration of axotomized neurons after spinal cord lesions at birth: a quantitative double-labeling study. Exp Neurol 123:1181321993Bernstein-Goral H Bregman BS: Spinal cord transplants support the regeneration of axotomized neurons after spinal cord lesions at birth: a quantitative double-labeling study. Exp Neurol 123:118–132 1993

    • Search Google Scholar
    • Export Citation
  • 6.

    Bollensen EScheidt PSchachner M: Production and characterization of monoclonal antibodies to the major peripheral myelin glycoprotein PO. J Neurochem 54:111011141990Bollensen E Scheidt P Schachner M: Production and characterization of monoclonal antibodies to the major peripheral myelin glycoprotein PO. J Neurochem 54:1110–1114 1990

    • Search Google Scholar
    • Export Citation
  • 7.

    Brandt HMApkarian AV: Biotin-dextran: a sensitive anterograde tracer for neuroanatomic studies in rat and monkey. J Neurosci Methods 45:35401992Brandt HM Apkarian AV: Biotin-dextran: a sensitive anterograde tracer for neuroanatomic studies in rat and monkey. J Neurosci Methods 45:35–40 1992

    • Search Google Scholar
    • Export Citation
  • 8.

    Bresnahan JC: An electron-microscopic analysis of axonal alterations following blunt contusion of the spinal cord of the rhesus monkey (Macaca mulatta). J Neurol Sci 37:59821978Bresnahan JC: An electron-microscopic analysis of axonal alterations following blunt contusion of the spinal cord of the rhesus monkey (Macaca mulatta). J Neurol Sci 37:59–82 1978

    • Search Google Scholar
    • Export Citation
  • 9.

    Bullitt EStofer WDVierck CJ et al: Reorganization of primary afferent nerve terminals in the spinal dorsal horn of the primate caudal to anterolateral chordotomy. J Comp Neurol 270:5495581988Bullitt E Stofer WD Vierck CJ et al: Reorganization of primary afferent nerve terminals in the spinal dorsal horn of the primate caudal to anterolateral chordotomy. J Comp Neurol 270:549–558 1988

    • Search Google Scholar
    • Export Citation
  • 10.

    Caroni PSchwab ME: Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1:85961988Caroni P Schwab ME: Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1:85–96 1988

    • Search Google Scholar
    • Export Citation
  • 11.

    Chapman CEWiesendanger M: Recovery of function following unilateral lesions of the bulbar pyramid in the monkey. Electroencephalogr Clin Neurophysiol 53:3743871982Chapman CE Wiesendanger M: Recovery of function following unilateral lesions of the bulbar pyramid in the monkey. Electroencephalogr Clin Neurophysiol 53:374–387 1982

    • Search Google Scholar
    • Export Citation
  • 12.

    Chen AXu XMBunge MB: Methylprednisolone administration improves axonal regeneration into Schwann cell grafts in transected adult rat thoracic spinal cord. Exp Neurology 138:2612761996Chen A Xu XM Bunge MB: Methylprednisolone administration improves axonal regeneration into Schwann cell grafts in transected adult rat thoracic spinal cord. Exp Neurology 138:261–276 1996

    • Search Google Scholar
    • Export Citation
  • 13.

    ChengHCao YOlson L: Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:5105131996Cheng H Cao Y Olson L: Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:510–513 1996

    • Search Google Scholar
    • Export Citation
  • 14.

    Darian-SmithIGalea MPDarian-Smith C: Manual dexterity: How does the cerebral cortex contribute? Clin Exper Pharmacol Physiol 23:9489951996Darian-Smith I Galea MP Darian-Smith C: Manual dexterity: How does the cerebral cortex contribute? Clin Exper Pharmacol Physiol 23:948–995 1996

    • Search Google Scholar
    • Export Citation
  • 15.

    David SAguayo AJ: Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:9319331981David S Aguayo AJ: Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–933 1981

    • Search Google Scholar
    • Export Citation
  • 16.

    Davidoff RA: The pyramidal tract. Neurology 40:3323391990Davidoff RA: The pyramidal tract. Neurology 40:332–339 1990

  • 17.

    Eidelberg E: Consequences of spinal cord lesions upon motor function, with special reference to locomotor activity. Prog Neurobiol 17:1852021981Eidelberg E: Consequences of spinal cord lesions upon motor function with special reference to locomotor activity. Prog Neurobiol 17:185–202 1981

    • Search Google Scholar
    • Export Citation
  • 18.

    Eidelberg EWalden JGNguyen LH: Locomotor control in macaque monkeys. Brain 104:6476631981Eidelberg E Walden JG Nguyen LH: Locomotor control in macaque monkeys. Brain 104:647–663 1981

    • Search Google Scholar
    • Export Citation
  • 19.

    Eidelberg EWoolf BKreinick CJet al: Role of the dorsal funiculi in movement control. Brain Res 114:4274381976Eidelberg E Woolf B Kreinick CJ et al: Role of the dorsal funiculi in movement control. Brain Res 114:427–438 1976

    • Search Google Scholar
    • Export Citation
  • 20.

    Galea MPDarian-Smith I: Corticospinal projection patterns following unilateral section of the cervical spinal cord in the newborn and juvenile macaque monkey. J Comp Neurol 381:2823061997Galea MP Darian-Smith I: Corticospinal projection patterns following unilateral section of the cervical spinal cord in the newborn and juvenile macaque monkey. J Comp Neurol 381:282–306 1997

    • Search Google Scholar
    • Export Citation
  • 21.

    Galea MPDarian-Smith I: Manual dexterity and corticospinal connectivity following unilateral section of the cervical spinal cord in the macaque monkey. J Comp Neurol 381:3073191997Galea MP Darian-Smith I: Manual dexterity and corticospinal connectivity following unilateral section of the cervical spinal cord in the macaque monkey. J Comp Neurol 381:307–319 1997

    • Search Google Scholar
    • Export Citation
  • 22.

    Glendinning DSVierck CJ: Lack of a proprioceptive deficit after dorsal column lesions in monkeys. Neurology 43:3633661993Glendinning DS Vierck CJ: Lack of a proprioceptive deficit after dorsal column lesions in monkeys. Neurology 43:363–366 1993

    • Search Google Scholar
    • Export Citation
  • 23.

    Godschalk MLemon RNNijs HGet al: Behavior of neurons in monkey peri-arcuate and precentral cortex before and during visually guided arm and hand movements. Exp Brain Res 44:1131161981Godschalk M Lemon RN Nijs HG et al: Behavior of neurons in monkey peri-arcuate and precentral cortex before and during visually guided arm and hand movements. Exp Brain Res 44:113–116 1981

    • Search Google Scholar
    • Export Citation
  • 24.

    Greenspan JDVierck CJRitz LA: Sensitivity to painful and nonpainful electrocutaneous stimuli in monkeys: effects of anterolateral chordotomy. J Neurosci 6:3803901986Greenspan JD Vierck CJ Ritz LA: Sensitivity to painful and nonpainful electrocutaneous stimuli in monkeys: effects of anterolateral chordotomy. J Neurosci 6:380–390 1986

    • Search Google Scholar
    • Export Citation
  • 25.

    Grill RMurai KBlesch Aet al: Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17:556055721997Grill R Murai K Blesch A et al: Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17:5560–5572 1997

    • Search Google Scholar
    • Export Citation
  • 26.

    Hepp-Reymond M-CTrouche EWiesendanger M: Effects of unilateral and bilateral pyramidotomy on a conditioned rapid precision grip in monkeys (Macaca fascicularis). Exp Brain Res 21:5195271974Hepp-Reymond M-C Trouche E Wiesendanger M: Effects of unilateral and bilateral pyramidotomy on a conditioned rapid precision grip in monkeys (Macaca fascicularis). Exp Brain Res 21:519–527 1974

    • Search Google Scholar
    • Export Citation
  • 27.

    King MALouis PMHunter BEet al: Biocytin, a versatile anterograde neuroanatomical tract-tracing alternative. Brain Res 497:3613671989King MA Louis PM Hunter BE et al: Biocytin a versatile anterograde neuroanatomical tract-tracing alternative. Brain Res 497:361–367 1989

    • Search Google Scholar
    • Export Citation
  • 28.

    Kucera PWiesendanger M: Do ipsilateral corticospinal fibers participate in the functional recovery following unilateral pyramidal lesions in monkeys? Brain Res 348:2973031985Kucera P Wiesendanger M: Do ipsilateral corticospinal fibers participate in the functional recovery following unilateral pyramidal lesions in monkeys? Brain Res 348:297–303 1985

    • Search Google Scholar
    • Export Citation
  • 29.

    Kunkel-Bagden EDai H-NBregman B: Recovery of function after spinal cord hemisection in newborn and adult rats: differential effects on reflex and locomotor function. Exp Neurol 116:40511992Kunkel-Bagden E Dai H-N Bregman B: Recovery of function after spinal cord hemisection in newborn and adult rats: differential effects on reflex and locomotor function. Exp Neurol 116:40–51 1992

    • Search Google Scholar
    • Export Citation
  • 30.

    Levi ADOBunge RP: Studies of myelin formation after transplantation of human Schwann cells into the severe combined immunodeficient mouse. Exp Neurol 130:41521994Levi ADO Bunge RP: Studies of myelin formation after transplantation of human Schwann cells into the severe combined immunodeficient mouse. Exp Neurol 130:41–52 1994

    • Search Google Scholar
    • Export Citation
  • 31.

    Levi ADOBunge RPLofgren JAet al: The influence of heregulins on human Schwann cell proliferation. J Neurosci 15:132913401995Levi ADO Bunge RP Lofgren JA et al: The influence of heregulins on human Schwann cell proliferation. J Neurosci 15:1329–1340 1995

    • Search Google Scholar
    • Export Citation
  • 32.

    Levi ADOGuenard VAebischer Pet al: The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J Neuroscience 14:130913191994Levi ADO Guenard V Aebischer P et al: The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J Neuroscience 14:1309–1319 1994

    • Search Google Scholar
    • Export Citation
  • 33.

    Levi ADOSonntag VKDickman JMet al: The role of cultured Schwann cell grafts in the repair of gaps within the peripheral nervous system of primates. Exp Neurol 143:25361997Levi ADO Sonntag VK Dickman JM et al: The role of cultured Schwann cell grafts in the repair of gaps within the peripheral nervous system of primates. Exp Neurol 143:25–36 1997

    • Search Google Scholar
    • Export Citation
  • 34.

    Liu CNChambers WW: Intraspinal sprouting of dorsal root axons. Arch Neurol Psychiatry 79:46611985Liu CN Chambers WW: Intraspinal sprouting of dorsal root axons. Arch Neurol Psychiatry 79:46–61 1985

    • Search Google Scholar
    • Export Citation
  • 35.

    McDonald JWLiu XZQu Yet al: Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:141014121999McDonald JW Liu XZ Qu Y et al: Transplanted embryonic stem cells survive differentiate and promote recovery in injured rat spinal cord. Nat Med 5:1410–1412 1999

    • Search Google Scholar
    • Export Citation
  • 36.

    Morrissey TKKleitman NBunge RP: Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci 11:243324421991Morrissey TK Kleitman N Bunge RP: Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci 11:2433–2442 1991

    • Search Google Scholar
    • Export Citation
  • 37.

    Nyberg-Hansen RRinvik E: Some comments on the pyramidal tract with special reference to its individual variations in man. Acta Neurol Scand 39:1301963Nyberg-Hansen R Rinvik E: Some comments on the pyramidal tract with special reference to its individual variations in man. Acta Neurol Scand 39:1–30 1963

    • Search Google Scholar
    • Export Citation
  • 38.

    Paino CLBunge MB: Induction of axonal growth into Schwann cell implants grafted into lesioned adult rat spinal cord. Exp Neurol 114:2542571991Paino CL Bunge MB: Induction of axonal growth into Schwann cell implants grafted into lesioned adult rat spinal cord. Exp Neurol 114:254–257 1991

    • Search Google Scholar
    • Export Citation
  • 39.

    Ramon-Cueto ACordero MISantos-Benito FFet al: Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25:4254352000Ramon-Cueto A Cordero MI Santos-Benito FF et al: Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25:425–435 2000

    • Search Google Scholar
    • Export Citation
  • 40.

    Ramon-Cueto APlant GWAvila J: Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 18:380338151998Ramon-Cueto A Plant GW Avila J: Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 18:3803–3815 1998

    • Search Google Scholar
    • Export Citation
  • 41.

    Richardson PMMcGuinness UMAguayo AJ: Peripheral nerve autografts to the rat spinal cord: studies with axonal tracing methods. Brain Res 237:1471621982Richardson PM McGuinness UM Aguayo AJ: Peripheral nerve autografts to the rat spinal cord: studies with axonal tracing methods. Brain Res 237:147–162 1982

    • Search Google Scholar
    • Export Citation
  • 42.

    Richardson PMMcGuinness UMAguayo AJ: Axons from CNS neurons regenerate into PNS grafts. Nature 284:2642651980Richardson PM McGuinness UM Aguayo AJ: Axons from CNS neurons regenerate into PNS grafts. Nature 284:264–265 1980

    • Search Google Scholar
    • Export Citation
  • 43.

    Tuszynski MEdgerton RDobkin B: Recovery of locomotion after experimental spinal cord injury: axonal regeneration or modulation of intrinsic spinal cord walking circuitry? J Spinal Cord Med 22:1431999Tuszynski M Edgerton R Dobkin B: Recovery of locomotion after experimental spinal cord injury: axonal regeneration or modulation of intrinsic spinal cord walking circuitry? J Spinal Cord Med 22:143 1999

    • Search Google Scholar
    • Export Citation
  • 44.

    Vierck CJ Jr: Absolute and differential sensitivities to touch stimuli after spinal cord lesions in monkeys. Brain Res 134:5295391977Vierck CJ Jr: Absolute and differential sensitivities to touch stimuli after spinal cord lesions in monkeys. Brain Res 134:529–539 1977

    • Search Google Scholar
    • Export Citation
  • 45.

    Vierck CJ Jr: Comparison of the effects of dorsal rhizotomy or dorsal column transection on motor performance of monkeys. Exp Neurol 75:5665751982Vierck CJ Jr: Comparison of the effects of dorsal rhizotomy or dorsal column transection on motor performance of monkeys. Exp Neurol 75:566–575 1982

    • Search Google Scholar
    • Export Citation
  • 46.

    Vierck CJ Jr: Comparison of forelimb and hindlimb motor deficits following dorsal column section in monkeys. Brain Res 146:2792941978Vierck CJ Jr: Comparison of forelimb and hindlimb motor deficits following dorsal column section in monkeys. Brain Res 146:279–294 1978

    • Search Google Scholar
    • Export Citation
  • 47.

    Vierck CJCooper BYLeonard CM: Motor capacities and deficiencies after interruption of the dorsal spinal columns in primates. Neurol Neurobiol 30:4194271987Vierck CJ Cooper BY Leonard CM: Motor capacities and deficiencies after interruption of the dorsal spinal columns in primates. Neurol Neurobiol 30:419–427 1987

    • Search Google Scholar
    • Export Citation
  • 48.

    Vierck CJ JrLuck MM: Loss and recovery of reactivity to nervous stimuli in monkeys with primary spinothalamic cordotomies, followed by secondary and tertiary lesions of other cord sectors. Brain 102:2332481979Vierck CJ Jr Luck MM: Loss and recovery of reactivity to nervous stimuli in monkeys with primary spinothalamic cordotomies followed by secondary and tertiary lesions of other cord sectors. Brain 102:233–248 1979

    • Search Google Scholar
    • Export Citation
  • 49.

    Vilensky JAMoore AM: Recovery of locomotion in monkeys with spinal cord lesions. J Motor Behav 24:2882961992Vilensky JA Moore AM: Recovery of locomotion in monkeys with spinal cord lesions. J Motor Behav 24:288–296 1992

    • Search Google Scholar
    • Export Citation
  • 50.

    Woolf CJ: Spinal injury. Overcoming inhibition. Nature 378:4394401995Woolf CJ: Spinal injury. Overcoming inhibition. Nature 378:439–440 1995

    • Search Google Scholar
    • Export Citation
  • 51.

    Xu XMGuenard VKleitman Net al: A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurology 134:2612721995Xu XM Guenard V Kleitman N et al: A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurology 134:261–272 1995

    • Search Google Scholar
    • Export Citation
  • 52.

    Xu X MGuenard VKleitman Net al: Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:1451601995Xu X M Guenard V Kleitman N et al: Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:145–160 1995

    • Search Google Scholar
    • Export Citation
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 322 188 22
Full Text Views 72 12 2
PDF Downloads 108 12 3
EPUB Downloads 0 0 0
PubMed
Google Scholar