Astrocytes Can Act as Permissive Substrates for the Growth of NGF-Sensitive Axons in Vivo

Abstract

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.