Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit.

Progenitor cell retention and release are largely governed by the binding of stromal-cell-derived factor 1 (SDF-1) to CXC chemokine receptor 4 (CXCR4) and by α4-integrin signaling. Both of these pathways are dependent on c-kit activity: the mobilization of progenitor cells in response to either CXCR4 antagonism or α4-integrin blockade is impaired by the loss of c-kit kinase activity; and c-kit-kinase inactivation blocks the retention of CXCR4-positive progenitor cells in the bone marrow. SDF-1/CXCR4 and α4-integrin signaling are also crucial for the retention of progenitor cells in the ischemic region, which may explain, at least in part, why clinical trials of progenitor cell therapy have failed to display the efficacy observed in preclinical investigations. The lack of effectiveness is often attributed to poor retention of the transplanted cells and, to date, most of the trial protocols have mobilized cells with injections of granulocyte colony-stimulating factor (G-CSF), which activates extracellular proteases that irreversibly cleave cell-surface adhesion molecules, including α4-integrin and CXCR4. Thus, the retention of G-CSF-mobilized cells in the ischemic region may be impaired, and the mobilization of agents that reversibly disrupt SDF-1/CXCR4 binding, such as AMD3100, may improve patient response. Efforts to supplement SDF-1 levels in the ischemic region may also improve progenitor cell recruitment and the effectiveness of stem cell therapy.