AMD3100 and CD26 Modulate Mobilization, Engraftment, and Survival of Hematopoietic Stem and Progenitor Cells Mediated by the SDF‐1/CXCL12‐CXCR4 Axis

Abstract

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.

Rescue from failed growth factor and/or chemotherapy HSC mobilization with G-CSF and plerixafor (AMD3100): an institutional experience

“…13,14,23,24,26 A dose-related increase in hematopoietic progenitor cells, colony forming unit-granulocyte macrophage, colony forming unit-granulocyte erythroid macrophage megakaryocyte and burst-forming unit-erythroid was seen in healthy volunteers at doses of 80, 160, 240 mg/kg. The synergistic effect of plerixafor and G-CSF has been examined in preclinical models, 17 healthy volunteers 18,23 and in patients with multiple myeloma or non-Hodgkin's lymphoma. 19,21,[24][25][26] These studies showed that there is a Table 1.…”

“…14,15 Subsequently, the role of plerixafor in the mobilization of PBSCs for auto-SCT was explored. 16,17 Plerixafor has been shown to rapidly increase circulating CD34 þ progenitor cells in preclinical murine models and healthy volunteers alone or in combination with G-CSF. [17][18][19] Other clinical trials were performed combining plerixafor and G-CSF for multiple myeloma or non-Hodgkin's lymphoma patients in first or second complete or PR planned for auto-SCT.…”

How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment

“…12,14,15 Bone marrow trophic, hypoxic pockets attract and retain HSC indirectly via HIF-1 among other paths. 14,16,17 HIF-1 to CXCR4-CXCL12 system CXCR4 is a 45 kDa outer cell membrane receptor for the 8 kDa chemokine CXCL12 (synonymous with the older term stromal-derived factor-1). 16,17,18 HIF-1 interacts with the promoter region of the CXCR4 gene, stimulating its transcription 19,20 and with the promoter region of the CXCL12 gene, stimulating its transcription.…”

“…14,16,17 HIF-1 to CXCR4-CXCL12 system CXCR4 is a 45 kDa outer cell membrane receptor for the 8 kDa chemokine CXCL12 (synonymous with the older term stromal-derived factor-1). 16,17,18 HIF-1 interacts with the promoter region of the CXCR4 gene, stimulating its transcription 19,20 and with the promoter region of the CXCL12 gene, stimulating its transcription. 21,22 HIF-1 also upregulates vascular endothelial growth factor expression 23,24 contributing to marrow neoangiogenesis.…”

“…This decreases CXCL12 gradient, loosening the grip on CD34 þ cells that then flood the circulation. 16,28,29 Glucagon-like peptide-1 is a 29-amino acid, 3.3 kDa peptide synthesized within ilium gut wall in response to food, that is also readily cleaved by DPP-4. 30 Since glucagon-like peptide-1 stimulates insulin secretion by pancreatic islet b cells, inhibitors of DPP-4 lower postprandial glucose levels in type II diabetes.…”