The CXCR4 agonist peptide, CTCE-0021, rapidly mobilizes polymorphonuclear neutrophils and hematopoietic progenitor cells into peripheral blood and synergizes with granulocyte colony-stimulating factor

Louis Pelus, Huimin Bian, Seiji Fukuda, Donald Wong, Ahmed Merzouk, Hassan Salari

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Objective. Mobilization of hematopoietic stem and progenitor cells (HSPC) by stromal cell-derived factor-1 (SDF-1) has been described; however, sustained adenoviral delivery or N-terminal modification was required for effect and could not be demonstrated with native protein. The aim of this study was to further investigate the SDF-1α/CXCR4 axis in HSPC mobilization using CTCE-0021, a cyclized CXCR4 agonist peptide, with comparable bioactivity and improved stability relative to SDF-1α. Methods. Peripheral blood cells and hematopoietic progenitor cells (HPC) were quantitated in mice administered single or multiple doses of CTCE-0021 or SDF-1α, or mobilized by granulocyte colony-stimulating factor (G-CSF) in combination with CTCE-0021. Proteases, cytokines, and receptors implicated in HSPC mobilization were evaluated to determine mechanism of action. Results. CTCE-0021 dose-dependently elevated blood neutrophils polymorphonuclear neutrophil [PMN] within 5 minutes that peaked after 1 hour and persisted for 24 hours. PMN mobilization could be maintained by daily dosing. CTCE-0021 mobilized colony-forming unit granulocyte macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM) that peaked within 1 hour after administration, and synergistically enhanced both PMN and HSPC mobilization when combined with G-CSF. Mobilization induced by CTCE-0021 was associated with rapid downregulation of CXCR4 expression on HPC. No appreciable changes in proteases implicated in HPC mobilization were observed. Significantly elevated plasma SDF-1 was detected in mobilized mice, which likely represents CTCE-0021. Conclusion. These studies indicate that CTCE-0021 is an efficient and rapid mobilizer of PMN and HPC when used alone and shows synergistic activity when used in combination with G-CSF. The mobilizing effect of this peptide appears to be mediated by downregulation of the CXCR4 receptor on HPC and altered chemokine gradient.

Original languageEnglish
Pages (from-to)295-307
Number of pages13
JournalExperimental Hematology
Volume33
Issue number3
DOIs
StatePublished - Mar 2005

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Granulocyte Colony-Stimulating Factor
Hematopoietic Stem Cells
Neutrophils
Chemokine CXCL12
Peptides
Hematopoietic Stem Cell Mobilization
Peptide Hydrolases
Down-Regulation
CTCE-0021
CXCR4 Receptors
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Cytokine Receptors
Megakaryocytes
Plasma Cells
Chemokines
Granulocytes
Monocytes
Blood Cells
Erythrocytes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

The CXCR4 agonist peptide, CTCE-0021, rapidly mobilizes polymorphonuclear neutrophils and hematopoietic progenitor cells into peripheral blood and synergizes with granulocyte colony-stimulating factor. / Pelus, Louis; Bian, Huimin; Fukuda, Seiji; Wong, Donald; Merzouk, Ahmed; Salari, Hassan.

In: Experimental Hematology, Vol. 33, No. 3, 03.2005, p. 295-307.

Research output: Contribution to journalArticle

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abstract = "Objective. Mobilization of hematopoietic stem and progenitor cells (HSPC) by stromal cell-derived factor-1 (SDF-1) has been described; however, sustained adenoviral delivery or N-terminal modification was required for effect and could not be demonstrated with native protein. The aim of this study was to further investigate the SDF-1α/CXCR4 axis in HSPC mobilization using CTCE-0021, a cyclized CXCR4 agonist peptide, with comparable bioactivity and improved stability relative to SDF-1α. Methods. Peripheral blood cells and hematopoietic progenitor cells (HPC) were quantitated in mice administered single or multiple doses of CTCE-0021 or SDF-1α, or mobilized by granulocyte colony-stimulating factor (G-CSF) in combination with CTCE-0021. Proteases, cytokines, and receptors implicated in HSPC mobilization were evaluated to determine mechanism of action. Results. CTCE-0021 dose-dependently elevated blood neutrophils polymorphonuclear neutrophil [PMN] within 5 minutes that peaked after 1 hour and persisted for 24 hours. PMN mobilization could be maintained by daily dosing. CTCE-0021 mobilized colony-forming unit granulocyte macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM) that peaked within 1 hour after administration, and synergistically enhanced both PMN and HSPC mobilization when combined with G-CSF. Mobilization induced by CTCE-0021 was associated with rapid downregulation of CXCR4 expression on HPC. No appreciable changes in proteases implicated in HPC mobilization were observed. Significantly elevated plasma SDF-1 was detected in mobilized mice, which likely represents CTCE-0021. Conclusion. These studies indicate that CTCE-0021 is an efficient and rapid mobilizer of PMN and HPC when used alone and shows synergistic activity when used in combination with G-CSF. The mobilizing effect of this peptide appears to be mediated by downregulation of the CXCR4 receptor on HPC and altered chemokine gradient.",
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T1 - The CXCR4 agonist peptide, CTCE-0021, rapidly mobilizes polymorphonuclear neutrophils and hematopoietic progenitor cells into peripheral blood and synergizes with granulocyte colony-stimulating factor

AU - Pelus, Louis

AU - Bian, Huimin

AU - Fukuda, Seiji

AU - Wong, Donald

AU - Merzouk, Ahmed

AU - Salari, Hassan

PY - 2005/3

Y1 - 2005/3

N2 - Objective. Mobilization of hematopoietic stem and progenitor cells (HSPC) by stromal cell-derived factor-1 (SDF-1) has been described; however, sustained adenoviral delivery or N-terminal modification was required for effect and could not be demonstrated with native protein. The aim of this study was to further investigate the SDF-1α/CXCR4 axis in HSPC mobilization using CTCE-0021, a cyclized CXCR4 agonist peptide, with comparable bioactivity and improved stability relative to SDF-1α. Methods. Peripheral blood cells and hematopoietic progenitor cells (HPC) were quantitated in mice administered single or multiple doses of CTCE-0021 or SDF-1α, or mobilized by granulocyte colony-stimulating factor (G-CSF) in combination with CTCE-0021. Proteases, cytokines, and receptors implicated in HSPC mobilization were evaluated to determine mechanism of action. Results. CTCE-0021 dose-dependently elevated blood neutrophils polymorphonuclear neutrophil [PMN] within 5 minutes that peaked after 1 hour and persisted for 24 hours. PMN mobilization could be maintained by daily dosing. CTCE-0021 mobilized colony-forming unit granulocyte macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM) that peaked within 1 hour after administration, and synergistically enhanced both PMN and HSPC mobilization when combined with G-CSF. Mobilization induced by CTCE-0021 was associated with rapid downregulation of CXCR4 expression on HPC. No appreciable changes in proteases implicated in HPC mobilization were observed. Significantly elevated plasma SDF-1 was detected in mobilized mice, which likely represents CTCE-0021. Conclusion. These studies indicate that CTCE-0021 is an efficient and rapid mobilizer of PMN and HPC when used alone and shows synergistic activity when used in combination with G-CSF. The mobilizing effect of this peptide appears to be mediated by downregulation of the CXCR4 receptor on HPC and altered chemokine gradient.

AB - Objective. Mobilization of hematopoietic stem and progenitor cells (HSPC) by stromal cell-derived factor-1 (SDF-1) has been described; however, sustained adenoviral delivery or N-terminal modification was required for effect and could not be demonstrated with native protein. The aim of this study was to further investigate the SDF-1α/CXCR4 axis in HSPC mobilization using CTCE-0021, a cyclized CXCR4 agonist peptide, with comparable bioactivity and improved stability relative to SDF-1α. Methods. Peripheral blood cells and hematopoietic progenitor cells (HPC) were quantitated in mice administered single or multiple doses of CTCE-0021 or SDF-1α, or mobilized by granulocyte colony-stimulating factor (G-CSF) in combination with CTCE-0021. Proteases, cytokines, and receptors implicated in HSPC mobilization were evaluated to determine mechanism of action. Results. CTCE-0021 dose-dependently elevated blood neutrophils polymorphonuclear neutrophil [PMN] within 5 minutes that peaked after 1 hour and persisted for 24 hours. PMN mobilization could be maintained by daily dosing. CTCE-0021 mobilized colony-forming unit granulocyte macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM) that peaked within 1 hour after administration, and synergistically enhanced both PMN and HSPC mobilization when combined with G-CSF. Mobilization induced by CTCE-0021 was associated with rapid downregulation of CXCR4 expression on HPC. No appreciable changes in proteases implicated in HPC mobilization were observed. Significantly elevated plasma SDF-1 was detected in mobilized mice, which likely represents CTCE-0021. Conclusion. These studies indicate that CTCE-0021 is an efficient and rapid mobilizer of PMN and HPC when used alone and shows synergistic activity when used in combination with G-CSF. The mobilizing effect of this peptide appears to be mediated by downregulation of the CXCR4 receptor on HPC and altered chemokine gradient.

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