Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism.
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.
Kinder
Michelle
M
The Wistar Institute, Philadelphia, PA 19104, USA.
Wei
Cong
C
Shelat
Suresh G
SG
Kundu
Mondira
M
Zhao
Liang
L
Blair
Ian A
IA
Puré
Ellen
E
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
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