Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism

Blood. 2010 Jun 17;115(24):5012-22. doi: 10.1182/blood-2009-09-243139. Epub 2010 Mar 31.

Abstract

Fatty acid metabolism governs multiple intracellular signaling pathways in many cell types, but its role in hematopoietic stem cells (HSCs) is largely unknown. Herein, we establish a critical role for 12/15-lipoxygenase (12/15-LOX)-mediated unsaturated fatty acid metabolism in HSC function. HSCs from 12/15-LOX-deficient mice are severely compromised in their capacity to reconstitute the hematopoietic compartment in competitive and serial reconstitution assays. Furthermore, we demonstrate that 12/15-LOX is required for the maintenance of long-term HSC quiescence and number. The defect in HSCs is cell-autonomous and associated with a selective reduction in 12/15-LOX-mediated generation of bioactive lipid mediators and reactive oxygen species and with a decrease in canonical Wnt signaling as measured by nuclear beta-catenin staining. These results have implications for development, aging, and transformation of the hematopoietic compartment.

Publication types

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

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / genetics*
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / genetics*
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Cell Count
  • Fatty Acids / metabolism*
  • Flow Cytometry
  • Gene Expression / physiology
  • Hematopoiesis / physiology
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / enzymology*
  • Interferon Regulatory Factors / genetics
  • Leukopenia / genetics
  • Leukopenia / metabolism
  • Leukopenia / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology
  • Wnt Proteins / metabolism

Substances

  • 12-15-lipoxygenase
  • Fatty Acids
  • Interferon Regulatory Factors
  • Reactive Oxygen Species
  • Wnt Proteins
  • interferon regulatory factor-8
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase