title: Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation.
abstract: Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis. CXCR4 was required for CLP positioning near Interleukin-7+(IL-7) cells and for optimal IL-7 receptor signaling. IL-7+cells expressed CXCL12 and the cytokine SCF, were mesenchymal progenitors capable of differentiation into osteoblasts and adipocytes, and comprised a minor subset of sinusoidal endothelial cells. Conditional Il7 deletion in mesenchymal progenitors reduced B-lineage committed CLPs, while conditional Cxcl12 or Scf deletion from IL-7+cells reduced HSC and MPP numbers. Thus, HSC maintenance and multilineage differentiation are distinct cell lineage decisions that are both controlled by HSC niches.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-002 Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Cordeiro Gomes
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan. Electronic address: thara@virus.kyoto-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Lim
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Herndler-Brandstetter
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Nevius
authors.affiliation: Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shizue
authors.initials: S
authors.lastname: Tani-Ichi
authors.affiliation: Autoimmune Genetics Laboratory, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium.
authors.forename: Susan
authors.initials: S
authors.lastname: Schlenner
authors.affiliation: Department of Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Richie
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: joao.pereira@yale.edu.
authors.forename: João Pedro
authors.initials: JP
authors.lastname: Pereira
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D002469:Cell Separation; D054426:Chemokine CXCL2 / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology*; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D054426:Chemokine CXCL2; D015851:Interleukin-7