title: Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING.
abstract: Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) for a variety of activities. Here, we report that c-di-GMP comprehensively regulated both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs while decreasing the number and repopulation capacity of long-term hematopoietic stem cells. Furthermore, we show that type I interferon acted as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while transforming growth factor-β was required for c-di-GMP-dependent splenic HSPC expansion. Our results define machinery underlying the dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling.
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Chiharu I
authors.initials: CI
authors.lastname: Kobayashi
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura-Ishizu
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Karigane
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haeno
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Kimiyo N
authors.initials: KN
authors.lastname: Yamamoto
authors.affiliation: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohteki
authors.affiliation: Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, Toyota 470-0392, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Department of Cell Biology and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore. Electronic address: sudato@z3.keio.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. Electronic address: keiyot@gmail.com.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism / Q000472:pathogenicity; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D055153:Stem Cell Niche / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid