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Immunity. 2016 Dec 20;45(6):1219-1231. doi: 10.1016/j.immuni.2016.11.004. Epub 2016 Nov 29.

Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation.

Author information

1
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.
2
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.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
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.
5
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
6
Autoimmune Genetics Laboratory, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium.
7
Department of Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA.
8
Division of Cellular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
9
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute.
10
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: joao.pereira@yale.edu.

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.

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