Guidance of DRG neurons in fate determination of bone marrow derived Schwann cells

Abstract

The bone marrow offers an autologous source of progenitor cells for use in remyelination therapy. Our success in deriving Schwann cells from bone marrow stromal cells suggests juxtacrine signals provided by embryonic dorsal root ganglia (DRG) neurons in the switch of Schwann cell-like cells (SCLCs) to fate commitment. In our search for the signals, immunocytochemical analysis found the Notch ligands,DLL-1 and Jagged-1, localized on the surface of DRG neurons whereas the receptor, Notch-1, was on bone marrow-derived SCLCs. In cocultures with DRG neurons, SCLCs indicated nuclear localization of the Notch intracellular domain (NICD), suggestive of ligand-activated Notch signaling. Concomitantly, increase in ErbB2/3 expression was revealed among SCLCs by mmunocytochemistry and confirmed by Western blotting. As cells achieved commitment to the Schwann cell fate, nuclear NICD returned to the basal level. When a ?-secretase inhibitor was used to inhibit Notch signaling, the increase inErbB2/3 expression among SCLCs was no longer effected and progress of SCLCs to the Schwann cell fate was significantly retarded. We therefore revealed an emerging role of Notch signaling in the upregulation of ErbB receptors for neuregulin-activated signaling as SCLCs transition into fate commitment. Without the co-culture with embryonic DRG neurons, however, the gliogenesis would switch to the oligodenroglial linage instead of Schwann cells.