2. Academic Validation
  3. Mobilization efficiency is critically regulated by fat via marrow PPARδ

Mobilization efficiency is critically regulated by fat via marrow PPARδ

  • Haematologica. 2021 Jun 1;106(6):1671-1683. doi: 10.3324/haematol.2020.265751.
Tomohide Suzuki 1,  Shinichi Ishii 1,  Masakazu Shinohara 2,  Yuko Kawano 1,  Kanako Wakahashi 1,  Hiroki Kawano 1,  Akiko Sada 1,  Kentaro Minagawa 1,  Michito Hamada 3,  Satoru Takahashi 4,  Tomoyuki Furuyashiki 5,  Nguan Soon Tan 6,  Toshimitsu Matsui 7,  Yoshio Katayama 8
Affiliations

Affiliations

  • 1 Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
  • 2 Division of Epidemiology; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
  • 3 Department of Anatomy and Embryology, Faculty of Medicine,.
  • 4 Department of Anatomy and Embryology, Faculty of Medicine; Transborder Medical Research Center (TMRC),; International Institute for Integrative Sleep Medicine (WPI-IIIS); Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8576.
  • 5 Division of Pharmacology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232; School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551.
  • 7 Department of Hematology, Nishiwaki Municipal Hospital, 652-1 Shimotoda, Nishiwaki 677-0043.
  • 8 Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017. katayama@med.kobe-u.ac.jp.
PMID: 33538151 DOI: 10.3324/haematol.2020.265751
Abstract

The mobilization efficiency of hematopoietic stem/progenitor cells from bone marrow (BM) to circulation by granulocyte colony-stimulating factor (G-CSF) is dramatically dispersed in humans and mice with no mechanistic lead for poor mobilizers. The regulatory mechanism for mobilization efficiency by dietary fat was assessed in mice. Fat-free diet (FFD) for 2 weeks greatly increased mobilization compared to normal diet (ND). The BM mRNA level of Peroxisome Proliferator-activated Receptor δ (PPARδ), a receptor for lipid mediators, was markedly up-regulated by G-CSF in mice fed with ND and displayed strong positive correlation with widely scattered mobilization efficiency. It was hypothesized that BM fat ligand for PPARδ might inhibit mobilization. The PPARδ Agonist inhibited mobilization in mice fed with ND and enhanced mobilization by FFD. Treatment with the PPARδ antagonist and chimeric mice with PPARδ+/- BM showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that BM PPARδ expression was enhanced by G-CSF mainly in mature/immature neutrophils. BM lipid mediator analysis revealed that G-CSF treatment and FFD resulted in the exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA). EPA induced the up-regulation of genes downstream of PPARδ, such as carnitine palmitoyltransferase-1α and angiopoietin-like protein 4 (Angptl4), in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with FFD in vivo. Treatment of wild-type mice with the anti-Angptl4 antibody enhanced mobilization together with BM vascular permeability. Collectively, PPARδ signaling in BM mature/immature neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.

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