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Cell. 2017 May 18;169(5):807-823.e19. doi: 10.1016/j.cell.2017.04.018. Epub 2017 May 4.

Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.

Author information

1
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany. Electronic address: n.cabezas@dkfz.de.
2
European Molecular Biology Laboratory, European Bioinformatics Institute (EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
3
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
4
LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
5
Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
6
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany.
7
Institute for Molecular Medicine, Stem Cells and Aging, Ulm University, 89081 Ulm, Germany.
8
Genomics Core Facility, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
9
Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, 4058 Basel, Switzerland.
10
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: a.trumpp@dkfz.de.

Abstract

Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT.

KEYWORDS:

ATRA; HSC; RNA-seq; diet; dormancy; hematopoietic stem cell; reporter; retinoic acid; single-cell; vitamin A

PMID:
28479188
DOI:
10.1016/j.cell.2017.04.018
[Indexed for MEDLINE]
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