Notch signaling mediates the switch to fate commitment of bone marrow-derived Schwann cells

Abstract

Our strategy of deriving fate-committed Schwann cells from bone marrow stromal cells (Shea et.al, 2010) supports that the cell-intrinsic switch to fate commitment depends on developing neurons of sensory ganglia. We therefore hypothesize that neurons recoverable from dorsal root ganglia (DRG, E14/15 rats) are at a stage that provides the juxtacrine/paracrine signals for the switch. Analysis of the DRG neurons found cell surface immunopositivities for DLL1, Jagged1 (ligands of Notch receptor) and Neuregulin-1 type III (ligand of ErbB receptors). While bone marrow-derived Schwann cell-like cells (SCLC) were immunopositive for Notch-1, coculture with DRG neurons resulted in progressive increase in ErbB2/B3 expression as revealed by immunocytochemistry and Western blotting. Following activation of the Notch1 receptor – Western blot revealed elevated level of Notch intracellular domain (NICD) during the switch to fate commitment; the level returned to basal when the bone marrow-derived cells tested true for commitment to the Schwann cell fate and in vitro myelination. Our results indicate that DRG neuron-SCLC interaction accomplishes DLL1/Jagged1 -Notch signaling that mediates SCLC expression of the ErbB receptors for signaling interaction with neuregulin-1 type III of DRG neurons. The findings promise the prospect of abundant fate-committed Schwann cells generated from an autologous source for use in nerve repair and regeneration.