Activation of the G-CSF and Flt-3 receptors protects hematopoietic stem cells from lethal irradiation

Philip R. Streeter, Layla Z. Dudley, William H. Fleming

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Objective. Synergy between Flt-3 ligand and G-CSF produces a marked expansion of hematopoietic progenitor cells and mobilizes large numbers of stem cells into the peripheral blood. To determine if the activation of the Flt-3 and G-CSF receptors enhances the regenerative capacity of the hematopoietic compartment, we evaluated whether activation of these receptors augments stem cell recovery following lethal doses of radiation. Methods. C57BL/6 mice received a single injection of the bi-functional Flt-3 and G-GSF agonist progenipoietin-1, 24 hours prior to exposure to 1100 cGy of gamma radiation. Survival, hematopoietic reconstitution, and competitive repopulation potential were evaluated. Results. All cytokine-treated mice survived for up to 9 months. Radioprotected recipients exhibited stable multilineage hematopoiesis and recovered normal numbers of T cells, B cells, and myelomonocytic cells in the blood, bone marrow, and thymus. Between 2 and 3 weeks following radiation, cytokine-treated mice demonstrated threefold higher serum hemoglobin levels, 10-fold higher nucleated blood cell counts, and 20-fold higher platelet counts compared to controls. Radioprotection of self-renewing hematopoietic stem cells was revealed by multilineage hematopoietic reconstitution following transplantation in a competitive repopulation assay. To further evaluate the extent of cytokine-induced radioprotective activity, a cohort of mice received a second cycle of cytokine treatment and a second exposure to radiation (1100 cGy). Survival of this serially irradiated group was 70% and analysis of the peripheral blood revealed sustained multilineage hematopoiesis. Conclusion. These results demonstrate that activation of both the Flt-3 and G-CSF receptors provides a high degree of radioprotection to the hematopoietic progenitor cell and stem cell compartment.

Original languageEnglish (US)
Pages (from-to)1119-1125
Number of pages7
JournalExperimental hematology
Volume31
Issue number11
DOIs
StatePublished - Nov 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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