TY - JOUR
T1 - Activation of the G-CSF and Flt-3 receptors protects hematopoietic stem cells from lethal irradiation
AU - Streeter, Philip R.
AU - Dudley, Layla Z.
AU - Fleming, William H.
PY - 2003/11
Y1 - 2003/11
N2 - 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.
AB - 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.
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U2 - 10.1016/S0301-472X(03)00257-1
DO - 10.1016/S0301-472X(03)00257-1
M3 - Article
C2 - 14585378
AN - SCOPUS:0142258088
SN - 0301-472X
VL - 31
SP - 1119
EP - 1125
JO - Experimental hematology
JF - Experimental hematology
IS - 11
ER -