Transforming growth factor ß induces bone marrow mesenchymal stem cell migration via noncanonical signals and N-cadherin.

ABSTRACT

Transforming growth factor-beta (TGF-ß) induces the migration and mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF-ß mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM-MSCs mediated by TGF-ß are unclear. In this study, we showed that TGF-ß activated noncanonical signaling molecules, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF-ß type I receptor in human BM-MSCs and murine BM-MSC-like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF-ß-mediated migration. These results suggested that the Smad-independent, noncanonical signals activated by TGF-ß were necessary for migration. We also showed that N-cadherin-dependent intercellular interactions were required for TGF-ß-mediated migration using functional inhibition of N-cadherin with EDTA treatment and a neutralizing antibody (GC-4 antibody) or siRNA-mediated knockdown of N-cadherin. However, N-cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF-ß. Therefore, these results suggested that the migration of BM-MSCs in response to TGF-ß was mediated through N-cadherin and noncanonical TGF-ß signals.