Inhibition of PDGF signal suppresses the fibrotic scar formation and promotes axonal regeneration in a mouse nigrostriatal lesion model.

Abstract

After traumatic injury to the central nervous system (CNS), meningeal fibroblasts migrate into the lesion site and synthesize extracellular matrix (ECM) molecules, leading to the formation of a fibrotic scar (FS). The FS prevents axonal regeneration by releasing inhibitory ECMs, including chondroitin sulfate proteoglycans, slits, and semaphorin 3 A. Platelet-derived growth factor (PDGF) has been implicated in fibrotic diseases, but its specific contribution to FS formation has remained unclear. In this study, we investigated the role of PDGF signaling in scar formation after CNS injury. In the lesioned mouse brain, PDGFRα and PDGFRβ were strongly expressed within the FS, whereas PDGF-B was detected in reactive astrocytes surrounding the lesion. Administration of AG1296, a PDGF signaling inhibitor, into the lesion site significantly reduced FS formation and allowed partial regeneration of transected dopaminergic axons. Complementary in vitro studies using rat meningeal fibroblasts demonstrated that PDGF signaling promoted both proliferation and migration of fibroblasts. Moreover, PDGF stimulation enhanced expression of transforming growth factor-β (TGF-β), a cytokine known to drive ECM deposition and scar formation. These findings provide the first direct evidence that inhibition of PDGF signaling suppresses FS formation and facilitates axonal regeneration after CNS lesioning. Our results suggest that PDGF signaling functions during the early phase of FS development by promoting fibroblast proliferation, migration, and TGF-β expression. Thus, targeting PDGF signaling may represent a promising therapeutic strategy for limiting scar formation and improving neural repair following human CNS injury.NEW & NOTEWORTHY Our research has revealed that PDGF signaling, which is known to be involved in various fibrotic diseases, also contributes to fibrotic scar formation-a barrier to nerve regeneration in the lesioned brain. This signaling plays a role in both the initiation and maintenance of fibrotic scar formation. Indeed, inhibiting PDGF signaling in vivo resulted in the disappearance of the fibrotic scar, thereby enabling nerve regeneration.