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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+.
| Abbreviations | ||
| AFRRI | = | Armed Forces Radiobiology Research Institute |
| 7ADD | = | 7-aminoactinomycin-D |
| Ak1 | = | adenylate kinase 1 |
| APC | = | allophycocyanin |
| BMMC | = | bone marrow mononuclear cells |
| CD | = | cluster differentiation marker |
| Ccna1 | = | Cyclin A1 |
| Cdkn | = | Cyclin-dependent kinase inhibitor |
| CFU-F | = | colony forming unit-fibroblast |
| D-PBS | = | Dulbecco's phosphate buffered saline |
| EDTA | = | ethylenediaminetetraacetic acid |
| ESR | = | electron spin resonance |
| Ter-119 | = | erythroid lineage marker |
| FITC | = | fluorescein isothiocyanate |
| Gr-1 and 7-4 | = | granulocyte-macrophage lineage specific antigens |
| LD50/30 | = | half lethal dose at 30 days |
| HPC | = | hematopoietic progenitor cells |
| HSC | = | hematopoietic stem cells |
| Hus1 | = | hydroxyurea sensitivity 1 |
| IMDM | = | Iscove's modified Dulbecco's medium |
| c-Kit | = | tyrosine kinase receptor for stem cell factor |
| LSK+ | = | Lin−Sca−1+c-Kit+ cells |
| LT-HSC | = | long-term pluripotent HSC |
| MACS | = | magnetic bead cell sorting |
| Lin+ | = | mature hematopoietic lineage cells |
| NIST | = | National Institute of Standards and Technology |
| Npm2 | = | nucleophosmin/nucleoplasmin 2 |
| Pmp22 | = | peripheral myelin protein 22 |
| PE | = | phycoerythrin |
| PEG | = | polyethyleneglycol |
| Ki67 | = | proliferation-associated Ki-67 protein |
| Prm1 | = | protamine 1 |
| qRT-PCR | = | quantitative real-time reverse transcription polymerase chain reaction |
| SD | = | standard deviation |
| Sca-1 | = | stem cell antigen-1 |
| ST-HSC | = | short-term progenitor HSC |
| Ct | = | threshold cycle |
| TBI | = | total body irradiation |
| Trp63 | = | transformation related protein 63. |
| Abbreviations | ||
| AFRRI | = | Armed Forces Radiobiology Research Institute |
| 7ADD | = | 7-aminoactinomycin-D |
| Ak1 | = | adenylate kinase 1 |
| APC | = | allophycocyanin |
| BMMC | = | bone marrow mononuclear cells |
| CD | = | cluster differentiation marker |
| Ccna1 | = | Cyclin A1 |
| Cdkn | = | Cyclin-dependent kinase inhibitor |
| CFU-F | = | colony forming unit-fibroblast |
| D-PBS | = | Dulbecco's phosphate buffered saline |
| EDTA | = | ethylenediaminetetraacetic acid |
| ESR | = | electron spin resonance |
| Ter-119 | = | erythroid lineage marker |
| FITC | = | fluorescein isothiocyanate |
| Gr-1 and 7-4 | = | granulocyte-macrophage lineage specific antigens |
| LD50/30 | = | half lethal dose at 30 days |
| HPC | = | hematopoietic progenitor cells |
| HSC | = | hematopoietic stem cells |
| Hus1 | = | hydroxyurea sensitivity 1 |
| IMDM | = | Iscove's modified Dulbecco's medium |
| c-Kit | = | tyrosine kinase receptor for stem cell factor |
| LSK+ | = | Lin−Sca−1+c-Kit+ cells |
| LT-HSC | = | long-term pluripotent HSC |
| MACS | = | magnetic bead cell sorting |
| Lin+ | = | mature hematopoietic lineage cells |
| NIST | = | National Institute of Standards and Technology |
| Npm2 | = | nucleophosmin/nucleoplasmin 2 |
| Pmp22 | = | peripheral myelin protein 22 |
| PE | = | phycoerythrin |
| PEG | = | polyethyleneglycol |
| Ki67 | = | proliferation-associated Ki-67 protein |
| Prm1 | = | protamine 1 |
| qRT-PCR | = | quantitative real-time reverse transcription polymerase chain reaction |
| SD | = | standard deviation |
| Sca-1 | = | stem cell antigen-1 |
| ST-HSC | = | short-term progenitor HSC |
| Ct | = | threshold cycle |
| TBI | = | total body irradiation |
| Trp63 | = | transformation related protein 63. |