FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
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DOI：
10.1016/j.cell.2007.01.003
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发表时间：
2007-01-26
期刊：
影响因子：
64.5
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
--
作者：
Tothova, Zuzana;Kollipara, Ramya;Gilliland, D. Gary
To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FoxO1, FoxO3, and FoxO4 in the adult hematopoietic system. FoxO-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1(+), c-Kit(+) (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO-deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO-deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.
