Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors
Abstract
Abstract Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development, partly by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet, whereas in mice, it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter from hematopoietic cells depleted ascorbate to undetectable levels in HSCs and multipotent hematopoietic progenitors (MPPs) without altering the plasma ascorbate levels. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potentials of MPPs, conferring the ability to reconstitute irradiated mice long term. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate deficiency confers MPPs with long-term self-renewal potential.
Article Details
Authors (14)
Stefano Comazzetto
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Daniel L. Cassidy
Andrew W. DeVilbiss
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Elise C. Jeffery
Bethany R. Ottesen
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Amanda R. Reyes
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Animesh Paul
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Suraj Bansal
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Stephanie Z. Xie
Sarah Muh
1Department of Pediatrics, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX
Thomas P. Mathews
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Brandon Chen
Zhiyu Zhao
Sean J. Morrison