Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy

被引:336
作者
Cabezas-Wallscheid, Nina [1 ,2 ,3 ]
Buettner, Florian [4 ]
Sommerkamp, Pia [1 ,2 ,3 ]
Klimmeck, Daniel [1 ,2 ,3 ]
Ladel, Luisa [1 ,2 ,3 ]
Thalheimer, Frederic B. [5 ,6 ]
Pastor-Flores, Daniel [7 ]
Roma, Leticia P. [7 ]
Renders, Simon [1 ,2 ,3 ]
Zeisberger, Petra [1 ,2 ,3 ]
Przybylla, Adriana [1 ,2 ,3 ]
Schoenberger, Katharina [1 ,2 ,3 ]
Scognamiglio, Roberta [1 ,2 ,3 ]
Altamura, Sandro [8 ]
Florian, Carolina M. [9 ]
Fawaz, Malak [5 ,6 ]
Vonficht, Dominik [1 ,2 ,3 ]
Tesio, Melania [1 ,2 ,3 ]
Collier, Paul [10 ]
Pavlinic, Dinko [10 ]
Geiger, Hartmut [9 ]
Schroeder, Timm [11 ]
Benes, Vladimir [10 ]
Dick, Tobias P. [7 ]
Rieger, Michael A. [5 ,6 ]
Stegle, Oliver
Trumpp, Andreas [1 ,2 ,3 ,12 ]
机构
[1] German Canc Res Ctr, Div Stem Cells & Canc, D-69120 Heidelberg, Germany
[2] DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany
[3] Heidelberg Inst Stem Cell Technol & Expt Med HI S, D-69120 Heidelberg, Germany
[4] EBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England
[5] Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, D-60590 Frankfurt, Germany
[6] Goethe Univ Frankfurt, Dept Med, Hematol Oncol, D-60590 Frankfurt, Germany
[7] German Canc Res Ctr, DKFZ ZMBH Alliance, Div Redox Regulat, D-69120 Heidelberg, Germany
[8] Heidelberg Univ, Dept Pediat Hematol Oncol & Immunol, D-69120 Heidelberg, Germany
[9] Ulm Univ, Inst Mol Med Stem Cells & Aging, D-89081 Ulm, Germany
[10] EMBL, Genom Core Facil, D-69117 Heidelberg, Germany
[11] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn D BSSE, CH-4058 Basel, Switzerland
[12] German Canc Consortium DKTK, D-69120 Heidelberg, Germany
基金
英国医学研究理事会;
关键词
SELF-RENEWAL; PROTEIN-SYNTHESIS; C-MYC; DIFFERENTIATION; EXPRESSION; HETEROGENEITY; TRANSCRIPTOME; QUIESCENCE; RECEPTORS; REVEALS;
D O I
10.1016/j.cell.2017.04.018
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:807 / +
页数:36
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