VITRONECTIN OVERRIDES A NEGATIVE EFFECT OF TNF-ALPHA ON ASTROCYTE MIGRATION

Morphogenesis and tissue repair require appropriate cross-talk between the cells and their surrounding milieu, which includes extracellular components and soluble factors, e.g., cytokines and growth factors. Th e present work deals with this communication needed for recovery after axotomy in the central nervous system (CNS). The failure of CNS axons to regenerate after axonal injury Iras been attributed, in part, to a strocyte failure to repopulate the injury site. The goal of this work was to provide an in vitro model to mimic the in vivo response of astr ocytes to nerve injury and to find ways to modulate this response and create a milieu that favors astrocyte migration and repopulation of th e injury site. In an astrocyte scratch wound model, we blocked astrocy te migration by tumor necrosis factor alpha (TNF-alpha). This effect c ould not be reversed by astrocyte migration-inducing factors such as t ransforming growth factor beta(1) (TGF-beta(1)) or by any of the teste d extracellular matrix (ECM) components (laminin and fibronectin) exce pt for vitronectin (Vn). Vn, added together with TNF-alpha, counteract ed the TNF-alpha blockage and allowed a massive migration of astrocyte s (not due to cell proliferation) beyond that allowed by Vn only. Hepa ran sulfate proteoglycans (HSPG) were shown to be involved in the migr ation. The results may be relevant to regeneration of CNS axons, and m ay also provide an example that an extracellular component (Vn) can ov ercome and neutralize a negative effect of a growth factor/cytokine (T NF-alpha) and can act in synergy with other features of this cytokine to promote a necessary function (e.g., cell migration) that is otherwi se inhibited.