Genistein induces radioprotection by hematopoietic stem cell quiescence.
OBJECTIVE
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.


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, (60)Co) of total body irradiation. Proliferation-associated Ki-67 protein/7-aminoactinomycin-D (Ki67/7AAD) cell cycle staining was used to differentiate between G(0), G(1), and S/G(2)/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 G(0) 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 G(1) and S/G(2)/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.


CONCLUSIONS
Pretreatment with genistein provides in vivo protection from acute myelotoxicity through extended quiescence followed by reduced senescence of marrow repopulating LSK(+).
Davis
Thomas A
TA
Regenerative Medicine Department, Combat Casualty Care Directorate, Naval Medical Research Center, Silver Spring, MD 20910, USA. thomas.davis1@med.navy.mil
Mungunsukh
Ognoon
O
Zins
Stephen
S
Day
Regina M
RM
Landauer
Michael R
MR
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D019070:Cell Lineage / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D007279:Injections, Subcutaneous; D051379:Mice; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*
D015415:Biomarkers; D011837:Radiation-Protective Agents; D019833:Genistein