Astrogliosis constitutes part of the central nervous system's physiological response to injury. Considered for decades to be a major challenge for brain repair, recent studies have highlighted it as a promoter of such repair mechanisms. Recently, our group demonstrated the ability of perlecan domain V (DV) to be a novel potential stroke therapy by its neuroprotective effects. However, the potential for DV to modulate astrogliosis has not been investigated. The aim of this study is to better understand the relevance of DV to astrogliosis using both in vitro and in vivo rodent models. Notably, under basal conditions, astrocytes express all three DV receptors described in the literature: integrin α2β1, α5β1, and α-dystroglycan (αDG). DV promoted astrocyte cell adhesion, cell migration as well as astrocyte stellation. Moreover, DV induced nerve growth factor (NGF) secretion through a αDG- and ERK-dependent pathway. In contrast, α2β1 or α5β1 mediated DV antiproliferative effects in astrocytes. NGF production after DV treatment acted as a strong anti-proliferative agent. Another remarkable effect of DV was that it decreased several markers of astrogliosis such as glial fibrillary acidic protein (GFAP), neurocan and phosphacan both in vitro and in vivo, suggesting the role of DV as a potential modulator of postinjury during late astrogliosis, and eventually the onset of glial scarring. Taken together, our study demonstrates the ability of DV to modulate key events of astrogliosis by promoting early astrogliosis and inhibiting glial scar formation, suggesting an additional therapeutic benefit of DV for recovery from stroke. © 2011 Wiley-Liss, Inc.