Intracellular calcium-binding protein S100A4 influences injury-induced migration of white matter astrocytes

Astrocytes play a crucial role in central nervous system (CNS) pathophysiology. White and gray matter astrocytes are regionally specialized, and likely to respond differently to CNS injury and in CNS disease. We previously showed that the calcium-binding protein S100A4 is exclusively expressed in white matter astrocytes and markedly up-regulated after injury. Furthermore, down-regulation of S100A4 in vitro significantly increases the migration capacity of white matter astrocytes, a property, which might influence their function in CNS tissue repair. Here, we performed a localized injury (scratch) in confluent cultures of white matter astrocytes, which strongly express S100A4, and in cultures of white matter astrocytes, in which S100A4 was down-regulated by transfection with short interference (si) S100A4 RNA. We found that S100A4-silenced astrocytes rapidly migrated into the injury gap, whereas S100A4-expressing astrocytes extended hypertrophied processes toward the gap, but without closing it. To explore the involvement of S100A4 in migration of astrocytes in vivo, we induced focal demyelination and transient glial cell elimination in the spinal cord white matter by ethidium bromide injection in S100A4 (-/-) and (+/+) mice. The results show that astrocyte migration into the demyelinated area is promoted in S100A4 (-/-) compared to (+/+) mice, in which a pronounced glial scar was formed. These data indicate that S100A4 reduces the migratory capacity of reactive white matter astrocytes in the injured CNS and is involved in glial scar formation after injury.