Astrocytes Can Act as Permissive Substrates for the Growth of NGF-Sensitive Axons in Vivo
Part of the
Altschul Symposia Series
book series (ALSS, volume 2)
The degree to which damaged axons successfully regenerate in the adult mammalian nervous system differs dramatically between the peripheral and central environments. In peripheral nerves, perturbed axons can regrow past the site of damage and extend through the nerve tube to reach denervated target sites. Schwann cells appear to be the predominant reason for this robust regeneration peripherally. These cells support neurite extension of most types of neurons in vitro (Noble et al., 1984; Fallon, 1985), since they express a varied array of surface molecules that are important for cell-cell adhesion (Seilheimer and Schachner, 1987). Schwann cells also produce nerve growth factor (NGF), the most potent growth-promoting substance found within the nervous system (Heumann et al., 1987; Matsuoka et al., 1991). In marked contrast, axon regeneration within the central nervous system (CNS) is impaired due to one or more of the following: the formation of glial scars in the immediate area of damage (Ramon y Cajal, 1928; Reier et al., 1983; Liuzzi and Lasek, 1987; Reier et al., 1987), the presence of myelin-associated inhibitory molecules (Schwab, 1990; Schwab and Caroni, 1988), and inadequate expression of growth-promoting factors and/or cell-cell adhesion molecules among neurons and glia. These features, acting alone or in concert with one another, contribute to the non-conducive nature of the adult CNS environment for axon regrowth in response to damage. Lesioned neurons, however, are able to extend new axons over considerable distances within a non-CNS milieu, including grafts of sciatic nerve (Richardson et al., 1980; David and Aguayo, 1981; Benfry and Aguayo, 1982, Hagg et al., 1990), amniotic membrane (Davis et al., 1987; Gage et al., 1988b) and fetal neural tissue (Kromer et al., 1981; Tuszynski et al., 1990a). Such tissues, therefore, must possess unique properties conducive for axon regrowth that are not available within the adult CNS. In fact, all three types of tissues have a number of permissive substrates for axon growth, e.g., Schwann cells in sciatic nerve, laminin in amniotic membrane, and immature astrocytes in fetal hippocampus. Furthermore, these materials contain variable levels of growth-promoting factors. Because tissues such as sciatic nerve possess both conducive substrates and trophic molecules, it is difficult to access the minimum requirement for the regeneration of adult CNS axons.
KeywordsNerve Growth Factor Sciatic Nerve Schwann Cell Cholinergic Neuron Amniotic Membrane
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Benfry, M., and Aguayo, A., 1982, Extensive elongation of axons from rat brain into peripheral nerve grafts. Nature
296: 150–152.CrossRefGoogle Scholar
Caramia, F., Angeletti, P.U., Levi-Montalcini, R., 1962, Experimental analysis of the mouse sub-maxillary salivary gland in relationship to its nerve growth factor content. Endocrinology
70: 915–922.PubMedCrossRefGoogle Scholar
Cohen, R., Levi-Montalcini, R., and Hamburger, V., 1954, A nerve growth-stimulating factor isolated from sarcomas 37 and 180. Proc. Natl. Acad. Sci. USA
40: 1014–1018.PubMedCrossRefGoogle Scholar
Cunningham, L.A., Hansen, J.T., Short, M.P., and Bohn, M.C., 1991a, Rat astrocytes containing a mouse NGF transgene enhance the survival of both young postnatal and adult adrenal chromaffin cells grafted into the adult rat striatum. Soc. Neurosci. Abstr.
17: 570.Google Scholar
Cunningham, L.A., Short, M.P., Vielkind, U., Breakefield, X.O., and Bohn, M.C., 1991b, Survival and differentiation within the adult mouse striatum of grafted rat pheochromocytoma (PC12) genetically modified to express recombinant 13-NGF. Exp. Neurol.
112: 174–182.PubMedCrossRefGoogle Scholar
David, S., and Aguayo, A., 1981, Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science
214: 931–933.PubMedCrossRefGoogle Scholar
Davis, G.E., Blaker, S.N., Engvall, E., Varon, S., Manthorpe, M., and Gage, F.H., 1987, Human amnion membrane serves as a substratum for growing axons in vitro
and in vivo. Science
236: 1106–1109.Google Scholar
Evercooren, A, B-V., Kleinman, H.K., Olmo, S., Marangos, P., Schwartz, J.P., and Dubois-Dalcq, M.E., 1982, Nerve growth factor, laminin, and fibronectin promote neurite growth in human fetal sensory ganglia cultures. J.Neurosci. Res
. 8: 179–193.CrossRefGoogle Scholar
Fallon, J.R., 1985, Preferential outgrowth of central nervous system neurites on astrocytes and Schwann cells as compared with nonglial cells in vitro. J. Cell Biol
. 100: 198–207.CrossRefGoogle Scholar
Fischer, W., Wictorin, K., Björklund, A., Williams, L.R., Varon, S., and Gage, F.H., 1987, Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature
329: 65–68.PubMedCrossRefGoogle Scholar
Gage, F.H., Wolff, J.A., Rosenberg, M.B., Xu, L., Yee, J.L., Shults, C., and Friedmann, T., 1987Google Scholar
Grafting genetically modified cells to the brain: possibilities for the future. Neuroscience
Gage, F.H., Armstrong, D.M., Williams, L.R., and Varon, S., 1988a, Morphologic response of axotomized septal neurons to nerve growth factor. J. Comp. Neurol.
269: 147–155.PubMedCrossRefGoogle Scholar
Gage, F.H., Blaker, S.N., Davis, G.E., Engvall, E., Varon, S., and Manthorpe, M., 1988b, Human amnion membrane matrix as a substratum for axonal regeneration in the central nervous system. Exp.Brain Res.
72: 371–380.PubMedCrossRefGoogle Scholar
Gage, F.H., Batchelor, P., Chen, K.S., Chin, D., Higgins, G.A., Koh, S., Deputy, S., Rosenberg, M.B., Fischer, W., and Björklund, A., 1989, NGF-receptor re-expression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. Neuron
2: 1177–1184.PubMedCrossRefGoogle Scholar
Hagg, T., Vahlsing, H.L., Manthorpe, M., and Varon, S., 1990, Septohippocampal cholinergic axonal regeneration through peripheral nerve bridges: Quantification and temporal development. Exp. Neurol.
109: 153–163.PubMedCrossRefGoogle Scholar
Hefti, F., 1986, Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J. Neurosci.
8: 2155–2162.Google Scholar
Heumann, R., Korsching, S., Bandtlow, C., and Thoenen, H., 1987, Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J. Cell Biol.
104: 1623–1631.PubMedCrossRefGoogle Scholar
Higgins, G.A., Koh, S., Chen, KC., and Gage, F.H., 1989, NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron
3: 247–256.PubMedCrossRefGoogle Scholar
Kawaja, M.D., Fagan, A.M., Firestein, B.L., and Gage, F.H., 1991, Intracerebral grafting of cultured autologous skin fibroblasts into the rat striatum: An assessment of graft size and ultrastructure. J. Comp. Neurol.
307, 695–706.PubMedCrossRefGoogle Scholar
Kawaja, M.D., and Gage, F.H., 1991, Reactive astrocytes are substrates for the growth of adult CNS axons in the presence of elevated levels of nerve growth factor. Neuron
7: 1019–1030.PubMedCrossRefGoogle Scholar
Kawaja, M.D., and Gage, F.H., 1992, Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J. Comp. Neurol.
317: 102–116.PubMedCrossRefGoogle Scholar
Kawaja, M.D., Rosenberg, M.B., Yoshida, K., and Gage, F.H., 1992, Somatic gene transfer of nerve growth factor promotes the survival of axotomized septal neurons and the regeneration of their axons in adult rats. J. Neurosci.
12: 2849–2864.PubMedGoogle Scholar
Koliatsos, V.E., Nauta, H.J.W., Clatterbuck, R.E., Holtzman, D.M., Mobley, W.C., and Price, D.L., 1990, Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey. J. Neurosci.
10: 3801–3813.PubMedGoogle Scholar
Kromer, L.F., 1987, Nerve growth factor treatment after brain injury prevents neuronal death. Science
235: 214–216.PubMedCrossRefGoogle Scholar
Kromer, L.F., Bjiirklund, A., and Stenevi, U., 1981, Innervation of embryonic hippocampal implants by regenerating axons of cholinergic septal neurons in the adult rat. Brain Res
. 210: 153–171.PubMedCrossRefGoogle Scholar
Levi-Montalcini, R., and Cohen, S., 1960, Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann. NY Acad. Sci.
85: 324–341.PubMedGoogle Scholar
Levi-Montalcini, R., Meyer, H., and Hamburger, V., 1954, In vitro
experiments on the effects of mouse sarcomas 180 and 37 on the spinal and sympathetic ganglia of the chick embryo. Cancer Res
. 14: 49–57.Google Scholar
Liuzzi, F.J., and Lasek, R.J., 1987, Astrocytes block axonal regeneration in mammals by activating the physiological stop pathway. Science
237: 642–645.PubMedCrossRefGoogle Scholar
Manthorpe, M., Engvall, E., Ruoslahti, E., Longo, F.M., Davis, G.E., and Varon, S., 1983, Laminin promotes neuritic regeneration from cultured peripheral and central neurons. J.Cell Biol.
97: 1882–1890.PubMedCrossRefGoogle Scholar
Matsuoka, I., Meyer, M., and Thoenen, H., 1991, Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: Comparison of Schwann cells with other cell types. J. Neurosci.
11: 3165–3177.PubMedGoogle Scholar
Noble, M., Fok-Seang, J., and Cohen, J., 1984, Glia are a unique substrate for the in vitro growth of central nervous system neurons. J. Neurosci.
4: 1892–1903.PubMedGoogle Scholar
Palmer, T.D., Rosman, G.J., Osbounre, W.R.A., and Miller, A.D., 1991, Genetically modified skin fibroblasts persist long after transplantation but gradually inactive introduced genes. Proc. Natl. Acad. Sci. USA
88: 1330–1334.PubMedCrossRefGoogle Scholar
Ramon y Cajal, S., 1928, “Degeneration and Regeneration of the Nervous System,” Oxford University Press, London.Google Scholar
Refer, P.J., Stensaas, L.J., and Guth, L., 1983, The astrocytic scar as an impediment to regeneration in the central nervous system, in: “Spinal Cord Reconstruction,” C.C. Kao, R.P. Bunge, and P.J. Reier, eds., Raven, New York.Google Scholar
Reier, P.J., Eng, L.F., and Jakeman, L., 1989, Reactive astrocyte and axonal outgrowth in the injured CNS: Is gliosis really an impediment to regeneration? in: “Neural Regeneration and Transplantation,” F.J. Seil, ed., Alan R. Liss, New York.Google Scholar
Richardson, P.M., and Ebendal, T., 1982, Nerve growth activities in rat peripheral nerve. Brain Res
. 246: 57–64.PubMedCrossRefGoogle Scholar
Richardson, P.M., McGuiness, U.M., and Aguayo, A.J., 1980, Axons from CNS neurons regenerate into PNS grafts. Nature
284: 264–265.PubMedCrossRefGoogle Scholar
Rogers, S.L., Letourneau, P.C., Palm, S.L., McCarthy, J., and Furcht, L.T., 1983, Neurite extension by peripheral and central nervous system neurons in response to substratum-bound fibronectin and laminin. Dev.Biol.
98: 212–220.PubMedCrossRefGoogle Scholar
Rosenberg, M.B., Friedmann, T., Robertson, R.C., Tuszynski, M., Wolff, J.A., Breakefield, X.O., and Gage, F.H., 1988, Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science
242: 1575–1578.PubMedCrossRefGoogle Scholar
Scharfmann, R., Axelrod, J.H., Verma, I.M., 1991, Long-term in vivo expression of retrovirusmediated gene transfer in mouse fibroblast implants. Proc. Natl. Acad. Sci. USA
88: 4626–4630.PubMedCrossRefGoogle Scholar
Schinstine, M., and Cornbrooks, C.J., 1990, Axotomy enhances the outgrowth of neuntes from embryonic rat septal-basal-forebrain neurons on a laminin substratum. Exp.Neurol.
108: 10–22.PubMedCrossRefGoogle Scholar
Schumacher, J.M., Short, M.P., Hyman, B.T., Breakefield, X.O., and Isacson, 0., 1991, Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience
45: 561–570.PubMedCrossRefGoogle Scholar
Schwab, M., 1990 Myelin-associated inhibitors of neurite growth and regeneration in the CNS. Trends Neurosci
. 13: 452–456.PubMedCrossRefGoogle Scholar
Schwab, M.E., and Caroni, P., 1988, Oligodendrocytes and CNS myelin are non-permissive sub- strates for neurite growth and fibroblast spreading in vitro. J. Neurosci
. 8: 2381–2393.Google Scholar
Seilheimer, B., and Schachner, M., 1987, Regulation of neural cell adhesion molecule expression on cultured mouse Schwann cells by nerve growth factor. EMBO J
. 6: 1611–1616.PubMedGoogle Scholar
Stromberg, L, Wetmore, C.J., Ebendal, T., Ernfors, P., Persson, H., and Olson, L., 1990, Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. J. Neurosci. Res.
25: 405–411.PubMedCrossRefGoogle Scholar
Tuszynski, M.H., Buzsaki, G., and Gage, F.H., 1990, NGF infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septo-hippocampal projection. Neuroscience
36: 33–44.PubMedCrossRefGoogle Scholar
Tuszynski, M.H., U, H.S., Amaral, D.G., and Gage, F.H., 1990b, Nerve growth factor infusion in primate brain reduces lesion-induced cholinergic neuronal degeneration. J. Neurosci.
10: 3604–3614.Google Scholar
Williams, L.R., Varon, S., Peterson, G.M., Wictorin, K., Fischer, W., Björklund, A., and Gage, F.H., 1986, Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria-fornix transection. Proc. Natl. Acad. Sci. USA
83: 9231–9235.PubMedCrossRefGoogle Scholar
Wolf, D., Richter-Landsberg, C., Short, M.P., Cepko, C., and Breakefield, X.O., 1988, Retrovirusmediated gene transfer of ß-nerve growth factor into mouse pituitary line AtT-20. Mol. Biol. Med.
5: 43–59.PubMedGoogle Scholar
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