Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex.

Following central nervous system injury, adult mammalian neurons do not regenerate through regions of scar formation. This regenerative failure is due in part to the inhibitory environment of the glial scar at the lesion site. Following injury, transforming growth factor beta (TGF-beta) is strongly induced and is important to many aspects of the response to injury, including deposition of extracellular matrix (ECM) in the glial scar. However, the pathways through which TGF-beta signals to mediate these effects are not known. In order to examine the contribution of the TGF-beta-induced transcription factor, Smad3, to formation of the glial scar after traumatic brain injury, we utilized mice that do not express Smad3. We report that Smad3 null mice heal stab wounds to the cerebral cortex more rapidly than do wild-type mice. In Smad3 null mice many aspects of glial scar formation and the immune response to injury were altered. Fewer neutrophils, macrophages/microglia, NG2-positive cells and GFAP-positive cells were detected immediately around the lesion in Smad3 null mice. Expression of fibronectin and laminin was also reduced. Injury-induced cell proliferation was significantly lower in Smad3 null mice around the lesion. There was no overall difference between wild-type and Smad3 null mice in immunoreactivity for TGF-beta(1) after injury. Thus, our experiments suggest that TGF-beta signaling through Smad3 contributes significantly to the immune response and scar formation after cortical stab wound injury, delaying recovery through multiple mechanisms.