AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis.
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 (HSCs) and progenitor (HPCs) 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 HPCs to the blood of mice; moreover, the combination of granulocyte colony-stimulating factor (G-CSF) with AMD3100 and MIP-1alpha/CCL3, given in a specific sequence, mobilizes the greatest number of HPCs 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 HSCs repopulating capacity of untreated donor cells; (3) the survival-enhancing effects of SDF-1/CXCL12 on HPCs subjected in vitro to delayed addition of growth factors (GFs) are 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 HPCs. These results demonstrate the means to increase the mobilization of HPCs, the engrafting capability of HSCs, and responsiveness of HPCs to the survival-enhancing activity of SDF-1/CXCL12, effects that may be of practical value.
Broxmeyer
Hal E
HE
Department of Microbiology and Immunology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. hbroxmey@iupui.edu
Hangoc
Giao
G
Cooper
Scott
S
Campbell
Timothy
T
Ito
Shigeki
S
Mantel
Charlie
C
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D018952:Antigens, CD34 / Q000096:biosynthesis; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000166:cytology; D019070:Cell Lineage; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D000080027:Cyclams; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000378:metabolism*
D019380:Anti-HIV Agents; D018952:Antigens, CD34; D001596:Benzylamines; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; D018819:Dipeptidyl Peptidase 4; C088327:plerixafor