Ascorbate regulates haematopoietic stem cell function and leukaemogenesis.
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis.
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DOI：
10.1038/nature23876
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发表时间：
2017-09-28
期刊：
影响因子：
64.8
通讯作者：
Morrison SJ
中科院分区：
文献类型：
--
作者：
Agathocleous M;Meacham CE;Burgess RJ;Piskounova E;Zhao Z;Crane GM;Cowin BL;Bruner E;Murphy MM;Chen W;Spangrude GJ;Hu Z;DeBerardinis RJ;Morrison SJ
干细胞的命运可以受到培养中代谢产物水平的影响，但尚不清楚正常组织中代谢产物水平的生理变化是否调节了体内干细胞的功能。我们开发了一种代谢组学方法来分析直接从组织中分离的稀有细胞群，并用它来比较造血干细胞(HSCs)和限制性造血祖细胞。每种造血细胞类型都有不同的代谢特征。人和小鼠的HSCs具有异常高的抗坏血酸水平，随着分化的进行，抗坏血酸水平下降。小鼠全身性抗坏血酸耗竭增加了HSC的频率和功能，部分原因是降低了TET2的功能，TET2是一种双加氧酶肿瘤抑制因子。抗坏血酸耗竭与Flt3ITD白血病突变协同作用，通过细胞自主和可能非细胞自主机制，以一种被饮食抗坏血酸逆转的方式加速白血病的发生。抗坏血酸通过TET2依赖和TET2非依赖机制发挥细胞自主作用，负向调节HSC功能和骨髓生成。因此，抗坏血酸在HSC内积聚，促进体内Tet功能，限制HSC的频率，抑制白血病的发生。
Stem cell fate can be influenced by metabolite levels in culture but it is unknown whether physiological variations in metabolite levels in normal tissues regulate stem cell function in vivo. We developed a metabolomics method for analysis of rare cell populations isolated directly from tissues and used it to compare haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which declined with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, partly by reducing Tet2 function, a dioxygenase tumor suppressor. Ascorbate depletion cooperated with Flt3ITD leukaemic mutations to accelerate leukaemogenesis, though cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate thus accumulates within HSCs to promote Tet function in vivo, limiting HSC frequency and suppressing leukaemogenesis.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
DOI：
10.1073/pnas.1612262113
发表时间：
2016-09-13
影响因子：
11.1
作者：
Liu, Minmin;Ohtani, Hitoshi;Jones, Peter A.
通讯作者：
Jones, Peter A.
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I
影响因子：
16.6
作者：
An J;González-Avalos E;Chawla A;Jeong M;López-Moyado IF;Li W;Goodell MA;Chavez L;Ko M;Rao A
通讯作者：
Rao A