Mobilization efficiency is critically regulated by fat via marrow PPARδ

Area of Science:

• Hematology
• Cell Biology
• Nutrition Science

Background:

• Hematopoietic stem/progenitor cell (HSPC) mobilization by granulocyte colony-stimulating factor (G-CSF) shows variable efficiency in humans and mice.
• The underlying mechanisms for poor mobilization remain unclear.
• Dietary factors, specifically fat, were investigated for their role in HSPC mobilization regulation.

Purpose of the Study:

• To elucidate the regulatory mechanism of dietary fat on HSPC mobilization efficiency.
• To investigate the role of peroxisome proliferator-activated receptor delta (PPARδ) in modulating HSPC mobilization.
• To identify specific lipid mediators involved in G-CSF-induced HSPC mobilization.

Main Methods:

• Mice were fed either a normal diet (ND) or a fat-free diet (FFD) and treated with G-CSF.
• PPARδ agonists and antagonists were administered to assess their effects on mobilization.
• Immunohistochemistry, flow cytometry, and lipid mediator analysis were performed.
• Chimeric mice and in vitro studies with neutrophils were utilized.

Main Results:

• A fat-free diet significantly increased HSPC mobilization compared to a normal diet.
• PPARδ expression in bone marrow neutrophils increased with G-CSF and correlated with mobilization efficiency.
• PPARδ activation inhibited mobilization on a normal diet but enhanced it on a fat-free diet.
• Eicosapentaenoic acid (EPA) depletion was observed, and EPA treatment modulated PPARδ downstream genes and inhibited mobilization.
• Anti-Angptl4 antibody treatment enhanced mobilization and bone marrow vascular permeability.

Conclusions:

• PPARδ signaling in bone marrow neutrophils, influenced by dietary fatty acids, negatively regulates HSPC mobilization.
• Angiopoietin-like protein 4 (Angptl4) is a key mediator in this inhibitory pathway.
• Dietary fat composition critically impacts HSPC mobilization efficiency via PPARδ-mediated pathways.