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


CONCLUSIONS
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.
BMT Program, Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, Ore 97239-3089, USA.
Philip R
PR
Streeter
Layla Z
LZ
Dudley
William H
WH
Fleming
D000818:Animals; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D011994:Recombinant Proteins; D051941:fms-Like Tyrosine Kinase 3
D003115:Colony-Stimulating Factors; D011518:Proto-Oncogene Proteins; D011837:Radiation-Protective Agents; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; C434603:progenipoietin-1; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3