[HTML][HTML] FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress

Z Tothova, R Kollipara, BJ Huntly, BH Lee… - Cell, 2007 - cell.com
Z Tothova, R Kollipara, BJ Huntly, BH Lee, DH Castrillon, DE Cullen, EP McDowell…
Cell, 2007cell.com
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 …
Summary
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.
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