Molecular and cellular aspects of axon-glia interaction in CNS regeneration

The relationships of neurons and non-neuronal cells are vital for the maintenance and function of neurons. Trauma alters these relationships causing proliferation of non-neuronal cells and, in adult mammalian CNS, presumably disturbs the environmental support needed for regeneration. A supportive environment can be restored by introducing a regenerating nerve to injured mammalian CNS. This response is probably due, at least in part, to diffusible substances secreted by the non-neuronal cells. We have obtained diffusible substances from either regenerating fish optic nerves or neonatal rabbit optic nerves and applied them around crushed adult rabbit optic nerves. This manipulation caused the adult nerve to show regenerative changes: a general increase of protein synthesis in the retinas; selective increase in synthesis of a few polypeptides in the retinas; sprouting from the retinas in vitro; increased viability of nerve fibers as shown by HRP staining; and the appearance of growth cones adjacent to glial limitans in the injured nerves. We termed these diffusible, active substances 'Growth Associated Triggering Factors' (GATFs). In addition to the phenomena described above, the active substances (obtained in the form of media conditioned by regenerating fish optic nerve or neonatal rabbit optic nerve) caused various other changes in the injured nerve itself: acceleration of non-neuronal cell proliferation; changes in the protein pattern, e.g. an increase in a 12 kDa polypeptide which might be a second mediator in the cascade of events leading to regeneration; increased laminin immunoreactive sites in the nerve; and the acquisition of growth supportive activity in media conditioned by the implanted injured nerves. Nerve growth factor (NGF) failed to induce such an effect whereas fibroblast growth factor (FGF) implanted around injured nerve had a significant effect on survival of the injured fibers. We would like to suggest that the non-neuronal cells have the capacity to control neuronal regeneration potential, provided they undergo the changes required for regeneration at the appropriate time. Any non-neuronal cell malfunction may lead to failure of regeneration. This brings an optimistic view to the study of regeneration as it suggests that mammalian CNS glial cells have the capacity to support regeneration provided they are stimulated at the right time with appropriate stimuli.