Mortality of acute events has improved, but more patients develop HF--a condition affecting up to 22 million people worldwide.
AMD3100 and CD26 Modulate Mobilization, Engraftment, and Survival of Hematopoietic Stem and Progenitor Cells Mediated by the SDF-1/CXCL12-CXCR4 Axis
Hal E Broxmeyer, Giao Hangoc, Scott Cooper, Timothy Campbell, Shigeki Ito, and Charlie Mantel
Ann. N.Y. Acad. Sci., March 14, 2007; .
Microbiology/Immunology; and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana, United States; Walther Cancer Institute, Indianapolis, Indiana, United States.
The chemokine stromal cell derived factor-1 (SDF-1/CXCL12) and its receptor, CXCR4, are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem (HSC) and progenitor (HPC) cells. Modulation of this ligand-receptor interaction may be of clinical utility. We now report that: (1) the CC chemokine, Macrophage Inflammatory Protein-1alpha (MIP-1alpha/CCL3) synergizes with AMD3100, (an antagonist of the binding of SDF-1/CXCL12 to CXCR4) to rapidly mobilize HPC to the blood of mice; moreover, the combination of granulocyte colony stimulating factor (G-CSF) with AMD3100 and MIP-1alpha/CCL3, given in specific sequence, mobilizes the greatest number of HPC compared to any combination of two of these mobilizing agents; (2) pretreatment of recipient mice with Diprotin A, an inhibitor of CD26/Dipeptidylpeptidase IV (DPPIV), enhances the competitive HSC repopulating capacity of untreated donor cells; (3) the survival enhancing effects of SDF-1/CXCL12 on HPC subjected in vitro to delayed addition of growth factors is mediated in part through the cell cycle related proteins p21(cip1/waf1) (as assessed using p21(cip1/waf1 -/-) and +/+ mice) and Mad2 (using Mad2 +/- and +/+ mice); and (4) deletion of CD26/DPPIV on mouse bone marrow cells increases the survival enhancing effects of SDF-1/CXCL12 on HPC. These results demonstrate means to increase mobilization of HPC, the engrafting capability of HSC, and responsiveness of HPC to the survival enhancing activity of SDF-1/CXCL12, effects that may be of practical value.
PMID: 17360804