CDK6 levels regulate quiescence exit in human hematopoietic stem cells.
CDK6 levels regulate quiescence exit in human hematopoietic stem cells.
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DOI：
10.1016/j.stem.2015.01.017
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发表时间：
2015-03-05
期刊：
影响因子：
23.9
通讯作者：
Dick, John E.
中科院分区：
文献类型：
--
作者：
Laurenti, Elisa;Frelin, Catherine;Xie, Stephanie;Ferrari, Robin;Dunant, Cyrille F.;Zandi, Sasan;Neumann, Andrea;Plumb, Ian;Doulatov, Sergei;Chen, Jing;April, Craig;Fan, Jian-Bing;Iscove, Norman;Dick, John E.
调节的血液生产是通过休眠的造血干细胞(HSC)亚群的分级组织实现的，这些亚群的自我更新潜力和分裂频率不同，其中长期(LT)-HSC分裂最少。HSC分裂动力学中这种差异背后的分子机制尚不清楚。我们在这里报道，在人类HSC亚群中，通过CDK6的表达水平对静止退出动力学进行了差异调节。LT-HSCs缺乏CDK6蛋白。短期(ST)-HSCs也是静止的，但含有高水平的CDK6蛋白，允许在有丝分裂刺激下快速进入细胞周期。在LT-HSCs中强制表达CDK6缩短了静止退出时间，并在不影响功能的情况下提供了竞争优势。计算模型表明，这种对静止退出动力学的独立控制本质上限制了LT-HSC的分裂，并保留了HSC池，以确保终身造血。因此，CDK6的差异表达是干细胞静止状态下的异质性的基础，而干细胞静止状态在功能上调节着这个高度再生的系统。人类长期(LT)和短期(ST)的造血干细胞都是静止的，长期(LT)和短期(ST)的HSC在分裂动力学上存在差异，CDK6的表达调节着退出静止的时间，对静止的差异性调节有助于维持造血。Laurenti等人。结果表明，人类HSC亚群退出静止的时间受CDK6表达水平的控制。这种差异化控制对HSC池的长期保存产生了影响。
Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6. LT-HSCs lack CDK6 protein. Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function. Computational modeling suggests that this independent control of quiescence exit kinetics inherently limits LT-HSC divisions and preserves the HSC pool to ensure lifelong hematopoiesis. Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system. Human long-term (LT) and short-term (ST) HSCs are equally quiescent LT- and ST-HSCs differ in division kinetics and expression of CDK6 CDK6 expression regulates the timing of exit from quiescence Differential regulation of quiescence helps maintain hematopoiesis The hematopoietic stem cell (HSC) compartment is heterogeneous in terms of cell cycle properties. Laurenti et al. show that the timing of exit from quiescence in human HSC subsets is controlled by CDK6 expression levels. This differential control has an impact on the long-term preservation of the HSC pool.
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影响因子：
5.9
作者：
Gazit, Roi;Garrison, Brian S.;Rao, Tata Nageswara;Shay, Tal;Costello, James;Ericson, Jeff;Kim, Francis;Collins, James J.;Regev, Aviv;Wagers, Amy J.;Rossi, Derrick J.
通讯作者：
Rossi, Derrick J.
影响因子：
30.5
作者：
Laurenti E;Doulatov S;Zandi S;Plumb I;Chen J;April C;Fan JB;Dick JE
通讯作者：
Dick JE
DOI：
10.1084/jem.20110447
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kataoka K;Sato T;Yoshimi A;Goyama S;Tsuruta T;Kobayashi H;Shimabe M;Arai S;Nakagawa M;Imai Y;Kumano K;Kumagai K;Kubota N;Kadowaki T;Kurokawa M
通讯作者：
Kurokawa M
影响因子：
64.5
作者：
Ren, SJ;Rollins, BJ
通讯作者：
Rollins, BJ
影响因子：
20.3
作者：
Placke, Theresa;Faber, Katrin;Froehling, Stefan
通讯作者：
Froehling, Stefan