Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors

造血 干细胞 祖细胞 生物 细胞生物学 移植 造血干细胞 癌症研究 免疫学 内科学 医学
作者
Stefano Comazzetto,Daniel Cassidy,Andrew W. DeVilbiss,Elise Jeffery,Bethany R. Ottesen,Amanda Reyes,Animesh Paul,Suraj Bansal,Stephanie Z. Xie,Sarah Muh,Thomas P. Mathews,Brandon Chen,Zhiyu Zhao,Sean J. Morrison
出处
期刊:Blood [American Society of Hematology]
标识
DOI:10.1182/blood.2024024769
摘要

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 while 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 MPPs without altering 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 multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. 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.

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