title: Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism.
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.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kinder
authors.forename: Cong
authors.initials: C
authors.lastname: Wei
authors.forename: Suresh G
authors.initials: SG
authors.lastname: Shelat
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D002452:Cell Count; D005227:Fatty Acids / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D050835:Interferon Regulatory Factors / Q000235:genetics; D007970:Leukopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D005227:Fatty Acids; D050835:Interferon Regulatory Factors; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D000099185:Interferon Regulatory Factor-8; C475064:12-15-lipoxygenase