Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy

Publication date: Available online 4 May 2017
Source:Cell
Author(s): Nina Cabezas-Wallscheid, Florian Buettner, Pia Sommerkamp, Daniel Klimmeck, Luisa Ladel, Frederic B. Thalheimer, Daniel Pastor-Flores, Leticia P. Roma, Simon Renders, Petra Zeisberger, Adriana Przybylla, Katharina Schönberger, Roberta Scognamiglio, Sandro Altamura, Carolina M. Florian, Malak Fawaz, Dominik Vonficht, Melania Tesio, Paul Collier, Dinko Pavlinic, Hartmut Geiger, Timm Schroeder, Vladimir Benes, Tobias P. Dick, Michael A. Rieger, Oliver Stegle, Andreas Trumpp
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.

Graphical abstract

Teaser

Metabolic inputs control the entry and exit of hematopoietic stem cells from dormancy and suggest the potential application of vitamin A in hematopoietic disorders and leukemias.


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