title: Glucose-Dependent Insulinotropic Polypeptide Receptor Deficiency Leads to Impaired Bone Marrow Hematopoiesis.
abstract: The bone marrow (BM) contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). The glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone that mediates postprandial insulin secretion and has anabolic effects on adipose tissue. Previous studies demonstrated altered bone microarchitecture in mice deficient for GIP receptor (Gipr-/-), as well as the expression of high-affinity GIP receptor by distinct cells constructing the BM HSPC niche. Nevertheless, the involvement of GIP in the process of BM hematopoiesis remains elusive. In this article, we show significantly reduced representation and proliferation of HSPC and myeloid progenitors in the BM ofGipr-/-mice. This was further manifested by reduced levels of BM and circulating differentiated immune cells in young and old adult mice. Moreover, GIP signaling was required for the establishment of supportive BM HSPC niches during HSPC repopulation in radioablated BM chimera mice. Finally, molecular profiling of various factors involved in retention, survival, and expansion of HSPC revealed significantly lower expression of the Notch-receptor ligands Jagged 1 and Jagged 2 in osteoblast-enriched bone extracts fromGipr-/-mice, which are important for HSPC expansion. In addition, there was increased expression of CXCL12, a factor important for HSPC retention and quiescence, in whole-BM extracts fromGipr-/-mice. Collectively, our data suggest that the metabolic hormone GIP plays an important role in BM hematopoiesis.
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Fernanda Dana
authors.initials: FD
authors.lastname: Mantelmacher
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Cohen
authors.affiliation: Bioinformatics Unit, G.S. Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel; and.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik Chor
authors.affiliation: Department of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Yuichiro
authors.identifier: 0000-0003-1623-0815
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; chenv@tlvmc.gov.il.
authors.forename: Chen
authors.identifier: 0000-0003-4222-5323
authors.initials: C
authors.lastname: Varol
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D005434:Flow Cytometry; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D011964:Receptors, Gastrointestinal Hormone / Q000172:deficiency
chemical_list: D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor