Cooperation of Matrix Metalloproteinases with the RhoA/Rho Kinase and Mitogen‐Activated Protein Kinase Kinase‐1/Extracellular Signal‐Regulated Kinase Signaling Pathways Is Required for the Sphingosine‐1‐Phosphate‐Induced Mobilization of Marrow‐Derived Stromal Cells

摘要: The ease of isolation and ex vivo culture marrow-derived stromal cells (MSCs) from adult bone marrow renders them a very promising source stem for gene transfer cell therapy. However, little is known about the signaling pathways that control their in mobilization subsequent biodistribution. Platelet-derived sphingosine-1-phosphate (S1P), bioactive lipid acts via G-protein-coupled-receptors, exerts strong chemoattraction upon MSCs through yet-uncharacterized pathways. We show S1P-induced migration morphological changes vitro require activities extracellular signal-regulated kinase (ERK), Rho (ROCK), matrix metalloproteinase (MMP) molecules. Specifically, remodeling MSC cytoskeleton led to rapid (<1 minute) formation actin stress fibers activation RhoA/ROCK pathway required catalytic activity MMPs. mitogen-activated protein kinase-1 (MEK1)/ERK also contributed induction redistribution paxillin at focal adhesions tyrosine phosphorylation adhesion an MMP-dependent manner. Moreover, MMP- ROCK-dependent molecular events are implicated regulation ERK. Our results demonstrate response S1P requires cooperation between MMP-mediated MEK1/ERK intracellular Therefore, characterization cellular factors underlying crucial achieve high efficacy therapeutic use.