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.

中文翻译：

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抗坏血酸缺乏症会增加造血干细胞和多能祖细胞的静止和自我更新


抗坏血酸（维生素 C）限制造血干细胞 （HSC） 功能并抑制白血病的发展，部分是通过促进 Tet2 肿瘤抑制基因的功能。在人类中，抗坏血酸是从饮食中获得的，而在小鼠中，它是在肝脏中合成的。在这项研究中，我们表明，从造血细胞中缺失 Slc23a2 抗坏血酸转运蛋白会在 HSC 和多能造血祖细胞 （MPP） 中将抗坏血酸消耗到检测不到的水平，而不会改变血浆抗坏血酸水平。Slc23a2 缺陷增加了移植到照射小鼠体内后 HSC 的重构电位和自我更新电位。Slc23a2 缺陷还增加了 MPP 的重组和自我更新电位，赋予了长期重建照射小鼠的能力。Slc23a2 缺陷型 HSCs 和 MPP 的分裂频率远低于对照 HSCs 和 MPP。特别是在静止的 Slc23a2 缺陷型 HSC 和 MPP 中观察到自我更新和重构电位增加。Slc23a2 缺陷对 MPP 自我更新的影响不是由 Tet2 功能降低介导的。因此，抗坏血酸调节 HSC 和 MPP 的静止状态并限制自我更新潜力，因此抗坏血酸缺乏赋予 MPP 具有长期的自我更新潜力。