Neurite outgrowth over resting and reactive astrocytes

A classic problem in CNS fiber regeneration is that the glial scar, generated after a lesion, is not crossed by regenerating axons. We know that reactive astrocytes are important in the formation of this barrier and that the barrier is not mechanical. However, its precise nature remains unclear. To study interactions of normal and reactive astrocytes with central neurites, we have attempted to create an in vitro model of the glial scar. We found the following: (1) Cultured astrocytes, independently of their lineage, morphology, immunological type and treatment with differentiating agents, induced profuse neurite outgrowth from various kinds of embryonic CNS neurons. The outgrowth was comparable to that elicited by laminin. (2) Membranes from isomorphic gliotic tissue (induced by deafferentation or excitotoxic injury and containing a large number of reactive astrocytes), inhibited central neurite outgrowth as powerfully as myelin. Reactive astrocyte membranes from areas of anisomorphic gliosis (following penetrating trauma) were permissive for neurite outgrowth, but growth was more limited than on cultured astrocyte membranes. (3) When given a choice, growing neurites actively avoided membranes from isomorphic gliosis (similar to myelin), while they seemed to follow anisomorphic membrane boundaries and crossed unhindered into membranes of cultured astrocytes. In conclusion, reactive glia seem to contain both inhibitory and neurite promoting molecules, the proportion of which depends on the way gliosis has been generated. For isomorphic reactive astrocytes the balance is inhibitory for central neurite outgrowth, while anisomorphic reactive astrocytes probably express inhibitory components at lower levels and the growth promoting factors predominate. Overall, our observations suggest that reactive astrocytes are still the major problem for axonal regeneration in the CNS.