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

The ease of isolation and ex vivo culture of marrow‐derived stromal cells (MSCs) from adult bone marrow renders them a very promising source of adult stem cells for gene transfer and cell therapy. However, little is known about the signaling pathways that control their in vivo mobilization and subsequent biodistribution. Platelet‐derived sphingosine‐1‐phosphate (S1P), a bioactive lipid that acts via G‐protein‐coupled‐receptors, exerts strong chemoattraction upon MSCs through yet‐uncharacterized signaling pathways. We show that the S1P‐induced migration and morphological changes of MSCs in vitro require the activities of extracellular signal‐regulated kinase (ERK), Rho kinase (ROCK), and matrix metalloproteinase (MMP) signaling molecules. Specifically, S1P‐induced remodeling of the MSC cytoskeleton led to the rapid (