Molecular and cellular aspects of nerve regeneration

Injury of an axon leads to at least four independent events, summarized in Figure 1: first, deprivation of the nerve cell body from target-derived or mediated substances, which leads to a derepressed or a permissive state; second, disruption of anterograde transport, with a resultant accumulation of anterogradely transported molecules; third, environmental response with possible consequent changes in constituents of the extracellular matrix and substances secreted from the surrounding cells; and fourth, appearance of growth inhibitors and modified protease activity. It seems that the first three of these events are obligatory, but not sufficient, i.e., they lead to a growth state only if the cell body is able to respond to the injury-induced signals from the environment (a and b). The regenerative state is characterized by alterations in protein synthesis and axonal transport and by sprouting activity. The subsequent elongation of the growing fibers depends on a continuous supply of appropriate growth factors. These factors are presumably anchored to the appropriate extracellular matrix that serves as a substratum for elongating fibers. It should be mentioned that the proliferating nonneuronal cells have a conducive effect on regeneration by forming a scaffold for the growing fibers. Accordingly, the lack of regeneration may stem from a deficiency in the ability of glial cells to provide the appropriate soluble components or from insufficient formation of extracellular matrix. In this respect, one may consider regeneration of an injured axon as a process which involves regeneration of both the nonneuronal cells and the supported axons. The regeneration of glial cells may fulfill the rules which are applied to regeneration of any other proliferating tissue. Furthermore, the processes of regeneration in the axon and the glial cells are mutually dependent. Perhaps the triggering factors provided by the nonneuronal cells affect the nonneuronal cells themselves by modulating their postlesion gliosis and thereby inducing their appropriate activation. In such a case, regeneration of nonneuronal cells may resemble an autocrine type of regulation that exists also during ontogeny. The growth regulation is shifted back to the paracrine type upon neuronal maturation or cessation of axonal growth. When the elongating fibers reach the vicinity of the target organ, they are under the influence of the target-derived factors, which guide the fibers and eventually cease their elongation.