Genistein induces radioprotection by hematopoietic stem cell quiescence |
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Authors: | Thomas A Davis Ognoon Mungunsukh Stephen Zins Regina M Day Michael R Landauer |
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Institution: | 1. Regenerative Medicine Department, Combat Casualty Care Directorate, Naval Medical Research Center, Silver Spring, MDthomas.davis1@med.navy.mil;3. Department of Pharmacology;4. Regenerative Medicine Department, Combat Casualty Care Directorate, Naval Medical Research Center, Silver Spring, MD;5. Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA |
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Abstract: | Purpose: In this study we addressed whether genistein-induced radioprotection in mice is associated with alterations of the cell cycle of hematopoietic stem and progenitor cells.Materials and methods: C57BL/6J female mice received a single subcutaneous injection of genistein (200 mg/kg) 24 h prior to a lethal dose (7.75 Gy, 60Co) of total body irradiation. Proliferation-associated Ki-67 protein/7-aminoactinomycin-D (Ki67/7AAD) cell cycle staining was used to differentiate between G0, G1, and S/G2/M in bone marrow cell populations negative for expression of mature hematopoietic lineage marker cells but positive for expression of stem cell antigen-1 and tyrosine kinase receptor for stem cell factor (Lin?Sca-1+cKit+, LSK+). Quantitative real-time polymerase chain reaction (qRT-PCR) microarrays were utilized to examine cell cycle specific genes.Results: At 24 h following radiation exposure, a greater percentage of LSK+ in genistein-treated mice accumulated in the G0 phase of the cell cycle, whereas a large percentage of LSK+ bone marrow cells from untreated and vehicle (PEG-400)-treated mice progressed into the G1 and S/G2/M phases. Moreover, the absolute number of marrow total LSK+, long-term LSK+, and short-term LSK+ increased 2.8, 12.1, and 4.2-fold, respectively, at 7 days post-irradiation in genistein-treated vs. untreated irradiated mice. Lin? cells from genistein-treated mice expressed fewer DNA damage responsive and cell cycle checkpoint genes than LSK+ from untreated or vehicle-treated mice.Conclusion: Pretreatment with genistein provides in vivo protection from acute myelotoxicity through extended quiescence followed by reduced senescence of marrow repopulating LSK+. |
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Keywords: | Hematopoietic stem cells irradiation myeloablation stem cell cycling hematopoietic reconstitution radioprotectants |
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