State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Sci Rep. 2017 Jul 10;7(1):4943. doi: 10.1038/s41598-017-05213-3.
3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a pivotal regulator in the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway that have been shown to play key roles in the functional development of B and T cells via activation of AGC protein kinases during hematopoiesis. However, the role of PDK1 in HSCs has not been fully defined. Here we specifically deleted the PDK1 gene in the hematopoietic system and found that PDK1-deficient HSCs exhibited impaired function and defective lineage commitment abilities. Lack of PDK1 caused HSCs to be less quiescent and to produce a higher number of phenotypic HSCs and fewer progenitors. PDK1-deficient HSCs were also unable to reconstitute the hematopoietic system. Notably, HSC function was more dependent on PDK1 than on mTORC2, which indicates that PDK1 plays a dominant role in the Akt-mediated regulation of HSC function. PDK1-deficient HSCs also exhibited reduced ROS levels, and treatment of PDK1-deficient HSCs with L-butathioninesulfoximine in vitro elevated the low ROS level and promoted colony formation. Therefore, PDK1 appears to contribute to HSC function partially via regulating ROS levels.
3-磷酸肌醇依赖的蛋白激酶 1（PDK1）是磷酸肌醇 3-激酶（PI3K）-Akt 信号通路中的一个关键调节因子，它通过在造血过程中激活 AGC 蛋白激酶，在 B 和 T 细胞的功能发育中发挥关键作用。然而，PDK1 在 HSCs 中的作用尚未完全确定。在这里，我们专门在造血系统中删除了 PDK1 基因，发现 PDK1 缺陷的 HSCs 表现出功能受损和谱系定向能力缺陷。缺乏 PDK1 导致 HSCs 静止性降低，产生更多的表型 HSCs 和更少的祖细胞。PDK1 缺陷的 HSCs 也无法重建造血系统。值得注意的是，HSC 的功能对 PDK1 的依赖性大于对 mTORC2 的依赖性，这表明 PDK1 在 Akt 介导的 HSC 功能调节中起主导作用。PDK1 缺陷的 HSCs 还表现出较低的 ROS 水平，体外用 L-丁硫氨酸亚砜亚胺处理 PDK1 缺陷的 HSCs 可提高低 ROS 水平并促进集落形成。因此，PDK1 似乎部分通过调节 ROS 水平来促进 HSC 的功能。
