Deposition of Scar Tissue in the Central Nervous System

  • M. Berry
  • W. L. Maxwell
  • A. Logan
  • A. Mathewson
  • P. Mcconnell
  • Doreen E. Ashhurst
  • G. H. Thomas
Part of the Acta Neurochirurgica Supplementum book series (NEUROCHIRURGICA, volume 32)


Standard parasagittal lesions were placed stercotactically in the cerebral hemispheres of neonatal and adult rats in order to compare scarring in the immature and mature animal. Lesions were examined by light and electron-microscopy and immunofluorescence to study the astrocyte reaction, collagen deposition, and the formation of the basement memebrane of the glia limitans.

Normal mature scarring characterized by the deposition of collagen, astrocyte end-feet alignment over a glia limitans, and the permanent presence of mesodermal cells (fibroblasts and macrophages) in the core of the lesion, does not occur in wounds before 8–10 days post-partum (dpp). Instead there is no deposition of collagen, and only a transitory astrocyte response occurs with the formation of an interrupted glia limitans. These latter features disappear with time so that the wound is ultimately obliterated by the growth of axons and dendrites through the lesion. Mature scarring is attained over 8–12 dpp when increasing amounts of collagen are deposited and a continuous permanent glia limitans is formed.

The acquisition of the mature response to injury from 8–12 dpp may be correlated with the presence of increasing titres of a fibroblast growth factor (FGF), derived from autolytic digestion of injured brain tissue. We have investigated FGF activity using a 3 T 3 fibroblast tissue culture assay to detect mitogenic activity in brain extracts from rats lesioned at different ages and from leukodystrophic mice which have no myelin.

Our results show that high titres of FGF are present in the developing brain long before myelination commences, and that normal levels of FGF are found in the brains of leukodystrophic mice which have no myelin. Scarring in brain lesions in these mutants is quite normal.


Brain lesions mesodermal/glial scarring maturation of scar tissue brain derived FGF leucodystrophic mutant mice shiverer myelin deficient quaking. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adrian, K., Williams, M. G., Cell proliferation in injured spinal cord. An electron microscopic study. J. comp. Neurol. 151 (1973), 1–24.PubMedCrossRefGoogle Scholar
  2. 2.
    Barrettt, C. P., Guth, L., Donati, E. J., Krikorian J. G., Astroglial reaction in the grey matter of lumbar segments after mid-thoracic transection of the adult rat spinal cord. Exp. Neurol. 13 (1981), 565–577.Google Scholar
  3. 3.
    Bernfield, M. R., Banerjee, S. D., The basal lamina of epithelial-mesenchymal morphogenetic interactions: In: Biology and chemistry of basement membranes (Kefalidcs, N. A., ed.), pp. 137–148. New York: Academic Press. 1978.Google Scholar
  4. 4.
    Bensted, J. P. M., Dobbing, J., Morgan, R. S., Reld, R. T. W., Payling Wright, G., Neurological development of myelination in the spinal cord of the chick embryo. J. Embryol. Exp. Morphol. 5 (1957), 428–437.Google Scholar
  5. 5.
    Berry, M., Henry, J., Response of neonatal CNS to injury. Neuropath. Appl. Neurobiol. 2 (1975), 166.Google Scholar
  6. 6.
    Bignami, A., Dahl, D., The astroglial response to stabbing. Immunofluorescence studies with antibodies to astrocyte specific protein (GFA) in mammalian and sub-mammalian vertebrates. Neuropath. Appl. Neurobiol. 2 (1976), 99–110.CrossRefGoogle Scholar
  7. 7.
    Bignami, A., Ralston, H., The cellular reaction to Wallerian degeneration in the central nervous system of the cat. Brain. Res. 13 (1969), 444–461.PubMedCrossRefGoogle Scholar
  8. 8.
    Bluemink, J. G., Maurik, P. van Lawson, K. A., Intimate cell contacts at the epitheliaVmesenchymal interface in embryonic mouse. J. Ultrastruct. Res. 55 (1976), 257–270.PubMedCrossRefGoogle Scholar
  9. 9.
    Boutwell, T. K., Factors promoting epidermal cell proliferation. In: The surgical wound (Duneen, P., Hildick-Smith, G., eds.), pp. 90–96. Philadelphia: Lea and Febiger. 1981.Google Scholar
  10. 10.
    Chiang, T. M., Whitaker, J. N., Seyer, J. M., Kang, A. H., Effect of peptides of bovine myelin basic protein in dermal fibroblasts. J. Neurosci. Res. 5 (1980), 439–445.PubMedCrossRefGoogle Scholar
  11. 11.
    Choi, B. M., Lapham, L. W., Radial glia in the human foetal cerebrum: A combined Golgi, immunofluorescent and electron microscopic study. Brain Res. 148 (1978), 295–311.PubMedCrossRefGoogle Scholar
  12. 12.
    Colmant, H. J., Allgemeine Histopathologie der Glia. Acta Neuropath. ( Berl.) Suppl. IV (1968), 61–76.Google Scholar
  13. 13.
    Cook, R. D., Wisniewski, H. M., The role of oligodendroglia and astroglia in Wallerian degeneration of the optic nerve. Brain Res. 61 (1973), 191–206.PubMedCrossRefGoogle Scholar
  14. 14.
    Duance, J. C., Restall, D. J., Beard, H., Bourne, F. J., Barley, A. J., The location of three collagen types in skeletal muscle. FEBS Lett. 79 (1977), 248–252.CrossRefGoogle Scholar
  15. 15.
    Dupouney, P., Jacque, C., Bourne, J. M., Cesselin, F., Privat, A., Baumann, N., Immunochemical studies on myelin basic protein in shiverer mouse devoid of major dense line of myelin. Neurosci. Lett. 12 (1979), 113–118.CrossRefGoogle Scholar
  16. 16.
    Friede, R. L., A histochemical study of DPN-diaphorase in human white matter; with some notes on myelination. J. Neurochem. 8 (1961), 17–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Gospodarowicz, D., Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3 T 3 cell growth. Nature 249 (1974), 123–127.PubMedCrossRefGoogle Scholar
  18. 18.
    Gospodarowicz, D., Humoral control of cell proliferation. The role of fibroblast growth factor in regeneration, angiogenesis, wound healing and neoplastic growth. In: Membranes and neoplasia: New approaches and strategies (Marchesi, V. T., ed.), pp. 1–19. New York: Alan R. Liss. 1976.Google Scholar
  19. 19.
    Gospodarowicz, D., Rudland, P., Lindstrom, J., Benirschke, K., Fibroblast growth factor, localization, purification, mode of action and physiological significance. Adv. Metab. Disord. 8 (1975), 301–335.PubMedGoogle Scholar
  20. 20.
    Gospodarowicz, D., Lui, G. -M., Cheng, J., Purification in high yield of brain fibroblast growth factor by preparative isoelectric focusing at pH 9.6. J. Biol. Chem. 257 (1982), 12266–12276.PubMedGoogle Scholar
  21. 21.
    Hogan, E. L., Animal models of genetic disorders of myelin. In: Myelin (Morell, P., ed.), pp. 489–520. New York: Plenum Press. 1977.Google Scholar
  22. 22.
    Hunt, D. K., Andrews, W. S., Halliday, B., Greenburg, G., Knoghton, D., Clark, R. A., Thakrai, K. K., Coagulation and macrophage stimulation of angiogenesis and wound healing. In: The surgical wound (Duneen, P., Hildick-Smith, G., eds.), pp. 1–18. Philadelphia: Lea and Febiger. 1981.Google Scholar
  23. 23.
    Ibrahim, M. Z. M., Glycogen and its related enzymes of metabolism in the central nervous system. Adv. Anat. Embryol. Biol. 52 (1975), 3–89.Google Scholar
  24. 24.
    Imamoto, K., Leblond, C. P., Presence of labelled monocytes, macrophages and microglia in association with a stab wound of the brain after an injection of bone marrow cells labelled with 3 H-uridine into rats. J. comp. Neurol. 174 (1977), 255–280.PubMedCrossRefGoogle Scholar
  25. 25.
    Jacobson, S., Sequence of myelination in the brain of the albino rat. A. Cerebral cortex, thalamus and related structures J. comp. Neurol. 121 (1963), 5–29.Google Scholar
  26. 26.
    Kellet, J. G., Tanaka, T., Rowe, J. M., Shiu, R. P. C., Friesen, H. G., The characterization of growth factor activity in human brain. J. Biol. Chem. 256 (1981), 54–58.Google Scholar
  27. 27.
    Krikorian, J. G., Guth, L., Donati, E. J., Origin of connective tissue scar in the transected rat spinal cord. Exp. Neurol. 72 (1981), 698–707.PubMedCrossRefGoogle Scholar
  28. 28.
    Landis, D. M. D., Reese, T. S., Arrays of particles in freeze fractured astrocytic membrane. J. Cell. Biol. 60 (1974), 316–328.PubMedCrossRefGoogle Scholar
  29. 29.
    Latov, N., Nilaver, G., Zimmerman, E. A., Johnson, W. G., Silverman, A.-J., Defendini, R., Cote, L., Fibrillar astrocytes proliferate to brain injury. Dev. Biol. 72 (1979), 381–384.PubMedCrossRefGoogle Scholar
  30. 30.
    Lemmon, S. K., Riley, M. C., Thomas, K. A., Hoover, G. A., Maciag, T., Bradshaw, R. A., Bovine fibroblast growth factor: comparison of brain and pituitary preparations. J. Cell. Biol. 95 (1982), 162–169.PubMedCrossRefGoogle Scholar
  31. 31.
    Lowry, O. H., Roosebrough, N. J., Farr, A. L., Randall, R. F., Protein measurements with Folin phenol reagent. J. Biol. Chem. 193 (1951), 265–275.PubMedGoogle Scholar
  32. 32.
    Matthieu, J.-M., Ginaleski, H., Friede, R. L., Cohen, S. R., Low myelin basic protein levels and normal myelin in peripheral nerves of myelin deficient mice (mid). Neuroscience 5 (1980), 2315–2320.PubMedCrossRefGoogle Scholar
  33. 33.
    Murabe, Y., Ibata, T., Sano, Y., Morphological studies on neuroglia. II. Response of glial cells to kianic acid-induced lesions. Cell Tissue Res. 216 (1981), 569–580.PubMedCrossRefGoogle Scholar
  34. 34.
    Nathan, C. F., Cohen, Z. A., Cellular components of inflammation, monocytes and macrophages. In: Textbook of rheumatology (Kelley, W. N., Harris. E. D., Jr., Ruddy, S., Sledge, C. B., eds.), pp. 136–162. Philadelphia: Saunders.Google Scholar
  35. 35.
    Nathan, C. F., Murray, H. W., Cohn, Z. A., The macrophage as an effector cell. N. Eng. J. Med. 303 (1980), 622–626.CrossRefGoogle Scholar
  36. 36.
    Persson, L., Cellular reactions to small cerebral stab wounds in the rat frontal lobe. Virch. Arch. B. Cell. Path. 22 (1976), 21–37.Google Scholar
  37. 37.
    Peters, A., Palay, S. L., Webster, H. de F., The fine structure of the nervous system. Philadelphia: Saunders. 1976.Google Scholar
  38. 38.
    Ross, R., The fibroblast and wound repair. Biol. Rev. 43 (1968), 51–96.Google Scholar
  39. 39.
    Schonbach, J., Hu, J. K., Friede, R. L., Cellular and chemical changes during myelination: Histologic, autoradiographic, histochemical and biochemical data on myelination in the pyramidal tract and corpus callosum of rat. J. comp. Neurol. 134 (1968), 21–38.PubMedCrossRefGoogle Scholar
  40. 40.
    Schultz, R. L., Pease, D. C., Cicatrix formation in rat cerebral cortex as revealed by electron microscopy. Amer. J. Path. 35 (1959), 1017–1042.PubMedGoogle Scholar
  41. 41.
    Seggie, J., Berry, M., Ontogeny of interhemispheric evoked potentials in the rat: Significance of myelination of the corpus callosum. Exptl. Neurol. 35 (1972), 215–232.CrossRefGoogle Scholar
  42. 42.
    Sidman, R. L., Rakic, P., Neuronal migration with special reference to developing human brain: A review. Brain Res. 6 2 (1973), 1–35CrossRefGoogle Scholar
  43. 43.
    Sievers, J., Mangold, U., Berry, M., Allen, C., Schlossberger, H. G., Experimental studies on cerebellar foliation. I. A qualitative morphological analysis of cerebellar foliation defects after neonatal treatment with 6-OHDA in the rat. J. comp. Neurol. 203 (1981), 751–769.Google Scholar
  44. 44.
    Skoff, R. P., The fine structure of pulse-labelled (3H-thymidine) cells in degenerating rat optic nerve. J. comp. Neurol. 161 (1975), 595–612.PubMedCrossRefGoogle Scholar
  45. 45.
    Skoff, R. P., Vaughn, J. E., An autoradiographic study of cellular proliferation in degenerating rat optic nerve. J. comp. Neurol. 141 (1971), 133–156.PubMedCrossRefGoogle Scholar
  46. 46.
    Spatz, H., Über die Vorgänge nach experimenteller Rückenmarksdurchtrennung mit besonderer Berücksichtigung der Unterschiede der Reaktionsweise des reifen and des unreifen Gewebes. In: Histologische and histopathologische Arbeiten über die Großhirnrinde ( Nissl, F., Alzheimer, A., eds.), pp. 49–354. Jena: G. Fischer. 1921.Google Scholar
  47. 47.
    Steedman, H. F., A new ribboning embedding medium for histology. Nature 197 (1957), 13–45.Google Scholar
  48. 48.
    Sternberger, L. A., In: Immuno-cytochemistry. New York: Wiley. 1979.Google Scholar
  49. 49.
    Sumi, S. M., Hager, H., Electron microscope study of experimental porencephaly. J. Neuropath. Exp. Neurol. 27 (1968), 1–38.CrossRefGoogle Scholar
  50. 50.
    Tennyson, V. M., Electron microscopic study of the developing neuroblast of the dorsal root ganglion of the rabbit embryo. J. comp. Neurol. 124 (: 965 ), 267–318.Google Scholar
  51. 51.
    Thomas, K. A., Riley, M. L., Lemmon, S. K., Baglan, N. C., Bradshaw, R. A., Brain-fibroblast growth factor: nonidentity with myelin basic protein fragments. J. Biol. Chem. 25, 5 (1980), 5517–5520.Google Scholar
  52. 52.
    Vaughn, J. E., Hinds, P. L., Skoff, R. P., Electron microscopic studies of Wallerian degeneration in the optic nerve of the rat. I. The multipotential glia. J. comp. Neurol. 140 (1970), 175–206.CrossRefGoogle Scholar
  53. 53.
    Vaughn, J. E., Pease, D. C., Electron microscopic studies of Wallerian degeneration in rat optic nerves. II. Astrocytes, oligodendrocytes and adventitial cells. J. comp. Neurol. 140 (1970), 207 226.Google Scholar
  54. 54.
    Wahl, S. M., Role of mononuclear cells in wound repair process. In: The surgical wound (Dineen, P., Hildick-Smith, G., eds.), pp. 63–74. Philadelphia: Lea and Febiger. 1981.Google Scholar
  55. 55.
    Westall, F. C., Lennon, V. A., Gospodarowicz, D., Brain-derived fibroblast growth factor: identity with a fragment of the basic protein of myelin. Proc. nat. Acad. Sei. U.S.A. 75 (1978), 4675–4678.CrossRefGoogle Scholar
  56. 56.
    Woodhams, P. L., Basco, E., Hajos, F., Csillag, A., Balazs, R., Radial glia in the developing mouse cerebral cortex and hippocampus. Anat. Embryol. 163 (1981), 331–343.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1983

Authors and Affiliations

  • M. Berry
    • 1
  • W. L. Maxwell
    • 2
  • A. Logan
    • 4
  • A. Mathewson
    • 1
  • P. Mcconnell
    • 3
  • Doreen E. Ashhurst
    • 2
  • G. H. Thomas
    • 4
  1. 1.Anatomy DepartmentGuy’s Hospital Medical SchoolLondonUK
  2. 2.Department of AnatomySt. George’s Hospital Medical SchoolLondonUK
  3. 3.Department of Human AnatomyUniversity of OxfordOxfordUK
  4. 4.Department of AnatomyUniversity of BirminghamBirminghamUK

Personalised recommendations