(251g) EphrinB2 Signaling by Astrocytes Regulates Neuronal Differentiation of Adult Neural Stem Cells in the Hippocampus

In pursuit of engineering biomaterials that effectively control stem cell differentiation, it is first necessary to elucidate the pertinent microenvironmental cues that regulate stem cells in vivo. In the mammalian brain, the birth of neurons from resident neural stem cells (NSCs), i.e. neurogenesis, persists throughout adulthood in both the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles. This process is tightly regulated, and very little is known about the molecular mechanisms that regulate neuronal differentiation of neural stem cells in the adult brain. It has been demonstrated that astrocytes within the adult hippocampus instruct neuronal differentiation of neural stem cells through growth factor signaling. We have discovered a novel juxtacrine signaling mechanism by which astrocytes further regulate adult neurogenesis. Traditionally, ephrin signaling is known to influence the spatial organization of cells by regulating cell migration, attraction and repulsion forces between contacting cells, and the formation and guidance of cellular protrusions. Our gain and loss of function studies, both in vitro and in vivo, indicate that astrocytic expression of the transmembrane ephrinB2 ligand plays a significant role in instructing proliferation and neuronal differentiation of NSCs within the SGZ of the adult hippocampus. Furthermore, our studies suggest that the neurogenic astrocyte ephrinB2 signal is transduced by direct interaction with the transmembrane EphB4 receptor expressed by neural stem cells. The discovery of ephrinB2's role in instructing neuronal differentiation of NSCs is one of the first systems shown to regulate neuronal differentiation of adult NSCs, and therefore, should be incorporated into engineered neurogenic cellular microenvironments used for neural tissue repair and regeneration.