Wang J, Alexander P, McKnight S L
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9152, USA.
Cold Spring Harb Symp Quant Biol. 2011;76:183-93. doi: 10.1101/sqb.2011.76.010835. Epub 2011 Nov 9.
Mouse embryonic stem (ES) cells are endowed with four unusual properties. They are exceedingly small, exhibiting an intracellular volume two to three orders of magnitude smaller than that of normal mammalian cells. Their rate of cell division, wherein cell doubling takes place in only 4-5 h, is more rapid than even the fastest growing cancer cell lines. They do not senesce. Finally, mouse ES cells retain pluripotency adequate to give rise to all cell types present in either gender of adult mice. We have investigated whether some or all of these unusual features might relate to the possibility that mouse ES cells exist in a specialized metabolic state. By evaluating the abundance of common metabolites as a function of the conversion of mouse ES cells into differentiated embryoid bodies, it was observed that the most radical changes in metabolite abundance related to cellular building blocks associated with one carbon metabolism. These observations led to the discovery that mouse ES cells use the threonine dehydrogenase (TDH) enzyme to convert threonine into acetyl-coenzyme A and glycine, thereby facilitating consumption of threonine as a metabolic fuel. Here we describe the results of a combination of nutritional and pharmacological studies, providing evidence that mouse ES cells are critically dependent on both threonine and the TDH enzyme for growth and viability.
小鼠胚胎干细胞具有四种不同寻常的特性。它们极其微小，细胞内体积比正常哺乳动物细胞小两到三个数量级。它们的细胞分裂速度极快，细胞仅需4 - 5小时就能翻倍，甚至比生长最快的癌细胞系还要快。它们不会衰老。最后，小鼠胚胎干细胞保持着足够的多能性，能够分化成成年小鼠雌雄两性体内所有的细胞类型。我们研究了这些不同寻常的特征中是否有部分或全部与小鼠胚胎干细胞处于特殊代谢状态的可能性有关。通过评估常见代谢物的丰度与小鼠胚胎干细胞向分化的胚状体转化过程之间的关系，我们观察到代谢物丰度最显著的变化与一碳代谢相关的细胞构件有关。这些观察结果促使我们发现，小鼠胚胎干细胞利用苏氨酸脱氢酶（TDH）将苏氨酸转化为乙酰辅酶A和甘氨酸，从而促进将苏氨酸作为代谢燃料的消耗。在此，我们描述了营养和药理学研究相结合的结果，提供了证据表明小鼠胚胎干细胞的生长和存活严重依赖于苏氨酸和TDH酶。
