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

Cell. 2007 Jan 26;128(2):325-39. doi: 10.1016/j.cell.2007.01.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Blood Cells / cytology
  • Blood Cells / drug effects
  • Blood Cells / metabolism*
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Bone Marrow / physiopathology
  • Cell Differentiation / genetics*
  • Cell Lineage / drug effects
  • Cell Lineage / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation / physiology
  • Hematopoiesis / drug effects
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / metabolism*
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Oxidative Stress / genetics*
  • Reactive Oxygen Species / metabolism
  • Transcription Factors / genetics

Substances

  • Antioxidants
  • FOXO4 protein, human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Foxo1 protein, mouse
  • Reactive Oxygen Species
  • Transcription Factors

Associated data

  • GEO/GSE6623