Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy

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


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.

MeSH terms

  • Animals
  • Biosynthetic Pathways
  • Cell Culture Techniques
  • Cell Cycle / drug effects
  • Cell Survival
  • Diet
  • Gene Expression Profiling
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Mice
  • Poly I-C / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction*
  • Single-Cell Analysis
  • Stress, Physiological
  • Tretinoin / pharmacology*
  • Vitamin A / administration & dosage*
  • Vitamin A / pharmacology
  • Vitamins / administration & dosage
  • Vitamins / pharmacology


  • GPRC5C protein, mouse
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • Vitamins
  • Vitamin A
  • Tretinoin
  • Poly I-C