FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress

Zuzana Tothova, Ramya Kollipara, Brian J. Huntly, Benjamin H. Lee, Diego H. Castrillon, Dana E. Cullen, Elizabeth P. McDowell, Suzan Lazo-Kallanian, Ifor R. Williams, Christopher Sears, Scott A. Armstrong, Emmanuelle Passegué, Ronald A. DePinho, D. Gary Gilliland

Research output: Contribution to journalArticle

1097 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)325-339
Number of pages15
JournalCell
Volume128
Issue number2
DOIs
StatePublished - Jan 26 2007

Keywords

  • DEVBIO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., Armstrong, S. A., Passegué, E., DePinho, R. A., & Gilliland, D. G. (2007). FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress. Cell, 128(2), 325-339. https://doi.org/10.1016/j.cell.2007.01.003