| Factors present in the extracellular environment are crucial to the success of nerve regeneration. One recently identified extracellular matrix molecule, thrombospondin (TSP), has the properties of a factor potentially involved in nerve regeneration. For instance, TSP is developmentally regulated in the mouse nervous system during periods of neuronal migration and axonal outgrowth, and it supports neurite outgrowth in vitro.;This work shows that TSP is present in nervous systems capable of nerve regeneration, has an expression pattern associated with active nerve regeneration, and promotes nerve regeneration in vivo. The pattern of expression of TSP was correlated with the regenerative potential of regions of mouse, goldfish, xenopus, and newt nervous systems, indicating that TSP is localized in a position relevant to nerve regeneration. Furthermore, changes in expression of TSP correlate with successful regeneration. First, following crush or transection injury to the mouse sciatic nerve, TSP expression increased distal to the trauma site, and was dramatically enriched in close association with regenerating neurites. After successful reinnervation, TSP returned to control levels. Second, following optic nerve crush in the goldfish, the level of TSP increased in the connective tissue septae along which regenerating axons grew. However, following crush injury of the mouse optic nerve, TSP was present in discreet clumps associated with macrophages but not in a pattern conducive to nerve regeneration. TSP also enhanced regeneration in an experimental paradigm. When polyethylene tubes filled with TSP, anti-TSP, laminin, or PBS were grafted into the mouse sciatic nerve, nerve cables regenerating through TSP filled grafts were consistently thicker and contained more axons than other groups. Addition of anti-TSP antibodies to the tubes significantly decreased Schwann cell migration.;Based on these results, TSP joins a small group of extracellular molecules, which are capable of supporting neurite outgrowth in vitro and whose expression corresponds with active nerve regeneration in vivo. The presence of TSP promotes nerve regeneration into polyethylene grafts, and addition of anti-TSP antibodies greatly inhibits nerve regeneration. Consistent with its expression pattern during neuronal development and its ability to support neurite outgrowth in vitro, TSP appears to play an important role in nerve regeneration in vivo. |
