Astrocyte-produced ephrins inhibit schwann cell migration via VAV2 signaling

Schwann cells are a promising candidate for bridging spinal cord injuries and remyelinating axons. However, grafted Schwann cells show little intermingling with host astrocytes and therefore limited migration from transplant sites. This leads to the formation of a sharp border between host astrocytes and Schwann cells, which results in axons stalling at the graft-host interface and failing to exit the graft. We investigated the possibility that Eph/ephrin interactions are involved in the segregation of Schwann cells and astrocytes and in limiting Schwann cell migration. Using reverse transcription-PCR, we have characterized the ephrin and Eph profile in cultured Schwann cells and astrocytes, showing that astrocytes produce all the ephrinAs and Schwann cells produce the receptors EphA2, EphA4, and EphA7. Several ephrinAs inhibit Schwann cell migration on laminin, with ephrinA5 being the most effective. Blocking the EphA receptors with excess EphA4-Fc increases Schwann cell migration on astrocytes and improves Schwann-astrocyte intermingling. We show that the action of ephrinA5 on Schwann cells is mediated via VAV2. Both clustered ephrinA5 and astrocyte contact increases the phosphorylation of VAV2 in Schwann cells. Knockdown of VAV2 abrogates the inhibitory effect of clustered ephrinA5 on migration and increases the ability of Schwann cells to migrate on astrocytes. In addition, we found a role for ephrinA5 in inhibiting Schwann cell integrin signaling and function. Overall, we suggest that Eph/ephrin interactions inhibit Schwann cell migration and intermingling with astrocytes via VAV signaling affecting integrin function.