Abstract
Postinjury recovery in most tissues requires an effective dialog with macrophages; however, in the mammalian central nervous system, this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure. We circumvented this by implanting macrophages, pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord. This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically evoked hind-limb muscle response. We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site, and by tracing descending fibers distally to it by anterograde labeling. In recovered rats, re-transection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts. Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy.
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References
Schwartz, M., Cohen, A., Stein-Izsak, C. & Belkin, M. Dichotomy of the glial cell response to axonal injury and regeneration FASEB J. 3, 2371–2378 (1989).
Aguayo, A.J., David, S. & Bray, G.M. Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents. J. Exp. Biol. 95, 231–240 (1981).
Schnell, L. & Schwab, M.E. Sprouting and regeneration of lesioned corticospinal tract fibres in the adult rat spinal cord. Eur. J. Neurosci. 5, 1156–1171 (1993).
Cheng, H., Cao, Y. & Olson, L. Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273, 510–513 (1996).
Chen, D.F., Jhaveri, S. & Schneider, G.E. Intrinsic changes in developing retinal neurons result in regenerative failure of their axons. Proc. Natl. Acad. Sci. USA 92, 7287–7291 (1995).
Grill, R., Murai, K., Blesch, A., Gage, F.H. & Tuszynski, M.H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal regrowth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572 (1997).
Harel, A. et al. Optic nerve regeneration in adult fish and apolipoprotein A-1. J. Neurochem. 52, 1218–1228 (1989).
Eitan, S. et al. Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration. Proc. Natl. Acad. Sci. USA 89, 5442–5446 (1992).
Eitan, S. & Schwartz, M. A transglutaminase that converts interleukin-2 into a factor cytotoxic to oligodendrocytes. Science 261, 106–108 (1993).
Eitan, S. et al. Recovery of visual response of injured adult rat optic nerves treated with transglutaminase. Science 264, 1764–1768 (1994).
Faber-Elman, A., Lavie, V., Schvartz, I., Shaltiel, S. & Schwartz, M. Vitronectin overrides a negative effect of TNF-alpha on astrocyte migration. FASEB J. 9, 1605–1613 (1995).
Faber-Elman, A., Solomon, A., Abraham, J.A., Marikovsky, M. & Schwartz, M. Involvement of wound-associated factors in rat brain astrocyte migratory response to axonal injury: in vitro simulation. J. Clin. Invest. 97, 162–171 (1996).
Lazarov-Spiegler, O., Solomon, A.S., Hirschberg, D.L., Lavie, V. & Schwartz, M. Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J. 10, 1296–1302 (1996).
Hirschberg, D.L. & Schwartz, M. Macrophage recruitment to acutely injured central nervous system is inhibited by a resident factor: a basis for an immune-brain barrier. J. Neuroimmunol. 61, 89–96 (1995).
Lotan, M. & Schwartz, M. Cross talk between the immune system and the nervous system in response to injury: implications for regeneration. FASEB J. 8, 1026–1033 (1994).
Perry, V.H., Brown, M.C. & Gordon, S. The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J. Exp. Med. 165, 1218–1223 (1987).
George, R. & Griffin, J.W. Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp. Neurol. 129, 225–236 (1994).
Streilein, J.W. Tissue barriers, immunosuppressive microenvironments and privileged sites: the eye's point of view. Reg. Immunol. 5, 253–268 (1993).
Schwartz, M., Hirschberg, D.L. & Beserman, P. Central nervous system regeneration and the immune system. Mol. Med. Today 1, 60–61 (1995).
Lazarov-Spiegler, O., Rapalino, O., Agranov, G. & Schwartz, M. Restricted inflammatory reaction in the CNS: a key impediment to regeneration. Mol. Med. Today, (in the press).
Basso, D.M. et al. MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. Multicenter animal spinal cord injury study. J. Neurotrauma 13, 343–359, (1996).
Basso, D.M., Beattie, M.S. & Bresnahan, J.C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21 (1995).
Basso, D.M., Beattie, M.S. & Bresnahan, J.C. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp. Neurol. 139, 244–256 (1996).
Brooks, C.M. & Peck, M.E. Effect of various cortical lesions on development of placing and hopping reactions in rats. J. Neurophysiol. 3, 66–73 (1940).
Goldberger, M.E., Bregman, B.S., Vierck, C.J. Jr., & Brown, M. Criteria for assessing recovery of function after spinal cord injury: behavioral methods. Exp. Neurol. 107, 113–117 (1990).
Kalderon, N. & Fuks, Z. Severed corticospinal axons recover electrophysiologic control of muscle activity after x-ray therapy in lesioned adult spinal cord. Proc. Natl. Acad. Sci. USA 93, 11185–11190 (1996).
Konrad, P.E. & Tacker, W.A. Jr., Suprathreshold brain stimulation activates non-corticospinal motor evoked potentials in cats. Brain Res. 522, 14–29 (1990).
Levy, W.J., McCaffrey, M., York, D.H. & Tanzer, F., Motor evoked potentials from transcranial stimulation of the motor cortex in cats. Neurosurgery 15, 214–227 (1984).
Nashmi, R., Imamura, H., Tator, C.H. & Fehlings, M.G. Serial recording of somatosensory and myoelectric motor evoked potentials: role in assessing functional recovery after graded spinal cord injury the rat. J. Neurotrauma 14, 151–159, 1997.
Blaugrund, E. et al. Axonal regeneration is associated with glial migration: comparison between the injured optic nerves of fish and rats. J. Comp. Neurol. 330, 105–112 (1993).
Young, W. Spinal cord regeneration. Science 273, 451 (1996).
Ben Zeev-Brann, A., Lazarov-Spiegler, O., Brenner, T. & Schwartz, M. Differential effects of central and peripheral nerves on macrophages and microglia. Glia, (in the press).
Lazarov-Spiegler, O., Solomon, A.S. & Schwartz, M. Peripheral nerve-stimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optnerve. Glia, (in the press).
Schwab, M.E. & Thoenen, H. Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J. Neurosci. 5, 2415–2423 (1985).
Davies, S.J., Fitch, M.T., Memberg, S.P., Hall, A.K., Raisman, G. & Silver, J. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683 (1997).
Schwab, M.E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).
Hikawa, N. & Takenaka, T. Myelin-stimulated macrophages release neurotrophic factors for adult dorsal root ganglion neurons in culture. Cell. Mol. Neurobiol. 16, 517–528 (1996).
Harel, A., Fainaru, M., Rubinstein, M., Tal, N. & Schwartz, M. Fish apolipoprotein-A-I has heparin binding activity; implication for nerve regeneration. J. Neurochem. 55, 1237–1243 (1990).
Ignatius, M.J. et al. Expression of apolipoprotein E during nerve degeneration and regeneration. Proc. Natl. Acad. Sci. USA 83, 1125–1129 (1986).
Bisby, M.A. & Chen, S., Wallerian degeneration in sciatic nerves of C57BL/Ola mice is associated with impaired regeneration of sensory axons. Brain Res. 530, 117–120 (1990).
Heumann, R. et al. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84, 8735–8739 (1987).
Stoll, G., Griffin, J.W., Li, C.Y. & Trapp, B.D. Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation. J. Neurocytol. 18, 671–683 (1989).
Xu, X.M., Chen, A., Guenard, V., Kleitman, N. & Bunge, M.B., Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J. Neurocytol. 26, 1–16 (1997).
Lazarov-Spiegler, O., Solomon, A.S. & Schwartz, M. The inflammatory reaction is an essential process for adult mammalian CNS regrowth. Vision Res. (in the press).
Bregman, B.S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).
Richardson, P.M., McGuinness, U.M. & Aguayo, A.J. Axons from CNS neurons regenerate into PNS grafts. Nature 284, 264–265 (1980).
Ye, J.H. & Houle, J.D. Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp. Neurol. 143, 70–81 (1997).
Rabchevsky, A.G. & Streit, W.J. Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J. Neurosci. Res. 47, 34–48 (1997).
Gale, K., Kerasidis, H. & Wrathall, J.R. Spinal cord contusion in the rat: behavioral analysis of functional neurologic impairment. Exp Neurol. 88, 123–134 (1985).
Kerasidis, H., Wrathall, J.R. & Gale, K. Behavioral assessment of fundamental deficit in rats with contusive spinal cord injury. J. Neurosci. Methods 20, 167–179 (1987).
Simpson, R.K. & Baskin, D.S. Corticomotor evoked potentials in acute and chronic blunt spinal cord injury in the rat: correlation with neurological outcome and histological damage. Neurosurgery 20, 131–137 (1987).
Gruner, J.A., Wade, C.K., Menna, G. & Stokes, B.T. Myoelectric evoked potentials versus locomotor recovery in chronic spinal cord injured rats. J. Neurotrauma. 10, 327–347 (1993).
Mediratta, N.K. & Nicoll, J.A. Conduction velocities of corticospinal axons in the rat studied by recording cortical antidromic responses. J. Physiol. Lond. 336, 545–561 (1983).
Nance, D.M. & Burns, J. Fluorescent dextrans as sensitive anterograde neuroanatomical tracers: applications and pitfalls. Brain Res. Bull. 25, 139–145 (1990).
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Rapalino, O., Lazarov-Spiegler, O., Agranov, E. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4, 814–821 (1998). https://doi.org/10.1038/nm0798-814
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DOI: https://doi.org/10.1038/nm0798-814
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