Page 169 - 2021_06-Haematologica-web

Hematopoiesis
Mobilization efficiency is critically regulated by fat via marrow PPARd
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1671-1683
Tomohide Suzuki,1 Shinichi Ishii,1 Masakazu Shinohara,2,3 Yuko Kawano,1° Kanako Wakahashi,1°° Hiroki Kawano,1° Akiko Sada,1 Kentaro Minagawa,1°°° Michito Hamada,4 Satoru Takahashi,4,5,6,7 Tomoyuki Furuyashiki,8 Nguan Soon Tan,9,10 Toshimitsu Matsui11 and Yoshio Katayama1
1Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 2Division of Epidemiology, Kobe University Graduate School of Medicine, Kobe, Japan; 3The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan; 4Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; 5Transborder Medical Research Center (TMRC), University of Tsukuba, Tsukuba, Japan; 6International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan; 7Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; 8Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Japan; 9Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore; 10School of Biological Sciences, Nanyang Technological University Singapore, Singapore and 11Department of Hematology, Nishiwaki Municipal Hospital, Nishiwaki, Japan
Current affiliations:
°YKaw and HK: Endocrine/Metabolism Division, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA;
°°KW: Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain;
°°°KM: Hematology & Oncology Division, Penn State College of Medicine, Hershey, PA, USA.
ABSTRACT
The efficiency of mobilization of hematopoietic stem/progenitor cells from bone marrow into the circulation by granulocyte colony-stim- ulating factor (G-CSF) is extremely varied in humans and mice and a mechanistic explanation for poor mobilizers is lacking. A mechanism of regulating mobilization efficiency by dietary fat was assessed in mice. Compared to a normal diet, a fat-free diet for 2 weeks greatly increased mobilization. The bone marrow mRNA level of peroxisome proliferator- activated receptor d (PPARd), a receptor for lipid mediators, was markedly upregulated by G-CSF in mice fed a normal diet and displayed a strong positive correlation with widely varied mobilization efficiency. It was hypothesized that the bone marrow fat ligand for PPARd might inhibit mobilization. A PPARd agonist inhibited mobilization in mice fed a normal diet and enhanced mobilization by a fat-free diet. Mice treated with a PPARd antagonist and chimeric mice with PPARd+/- bone marrow showed enhanced mobilization. Immunohistochemical staining and flow cytome- try revealed that bone marrow PPARd expression was enhanced by G-CSF mainly in mature/immature neutrophils. Analysis of bone marrow lipid mediators revealed that G-CSF treatment and a fat-free diet resulted in exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid. Eicosapentaenoic acid induced the upregulation of genes down- stream of PPARd, such as Cpt1α and Angptl4, in mature/immature neu- trophils in vitro and inhibited enhanced mobilization in mice fed with a fat- free diet in vivo. Treatment of wild-type mice with anti-Angptl4 antibody enhanced mobilization as well as bone marrow vascular permeability. Collectively, PPARd signaling in mature/immature bone marrow neu- trophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.
Correspondence:
YOSHIO KATAYAMA
katayama@med.kobe-u.ac.jp
Received: July 3, 2020. Accepted: January 19, 2021. Pre-published: February 4, 2021.
https://doi.org/10.3324/haematol.2020.265751
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2021; 106(6)
1671
ARTICLE