Enhanced c-Met activity promotes G-CSF induced mobilization of hematopoietic progenitor cells via ROS signaling.

Mechanisms governing stress-induced hematopoietic progenitor cell mobilization are not fully deciphered. We report that during G-CSF-induced mobilization c-Met expression and signaling are up-regulated on immature bone marrow progenitors. Interestingly, SDF-1/CXCR4 signaling induced HGF production and c-Met activation. We found that c-Met inhibition reduced mobilization of both immature progenitors and the more primitive Sca-1+/c-Kit+/Lin- cells and interfered with their enhanced chemotactic migration to SDF-1. c-Met activation resulted in cellular accumulation of reactive oxygen species (ROS) via mTOR inhibition of FOXO3a. Blockage of mTOR or ROS signaling impaired c-Met-mediated mobilization. Our data reveal dynamic c-Met expression and function in the bone marrow and show that enhanced c-Met signaling is crucial to facilitate stress-induced mobilization of progenitor cells as part of host defense and repair mechanisms.