[HTML][HTML] FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
Cell, 2007•cell.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 …
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.
cell.com