The cell-cycle state of stem cells determines cell fate propensity.
The cell-cycle state of stem cells determines cell fate propensity.
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DOI：
10.1016/j.cell.2013.08.031
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发表时间：
2013-09-26
期刊：
影响因子：
64.5
通讯作者：
Vallier L
中科院分区：
文献类型：
--
作者：
Pauklin S;Vallier L
干细胞的自我更新和分化从根本上与细胞周期进程相关，以实现组织特化、器官稳态和潜在的肿瘤发生。然而，技术上的挑战削弱了协调细胞命运选择和细胞周期进程的分子相互作用的研究。在这里，我们通过在人类多能干细胞中使用FUCCI报告系统来绕过这些限制，并表明它们的分化能力在细胞周期的进展过程中有所不同。这些机制由细胞周期调节因子细胞周期蛋白D1-3控制，细胞周期蛋白D1-3控制分化信号，如TGF-β-Smad 2/3途径。相反，使用小分子的细胞周期操纵指导hPSC的分化，并提供了产生具有临床意义的细胞类型的方法。我们的研究结果表明，细胞命运的决定与细胞周期机制密切相关，并揭示了在发育组织中同步分化和增殖的机制。细胞命运决定是细胞周期依赖性的通过细胞周期蛋白D-CDK 4/6控制内胚层与神经外胚层分化细胞周期蛋白Ds控制TGF-β-Smad 2/3转录活性hPSC的分化可以通过操纵细胞周期来指导细胞命运决定在干细胞开始分化时受到干细胞的细胞周期状态和细胞周期蛋白D活性的影响。细胞周期蛋白D通过TGF-β-Smad信号传导作用以改变内胚层相对于神经外胚层命运的倾向。
Self-renewal and differentiation of stem cells are fundamentally associated with cell-cycle progression to enable tissue specification, organ homeostasis, and potentially tumorigenesis. However, technical challenges have impaired the study of the molecular interactions coordinating cell fate choice and cell-cycle progression. Here, we bypass these limitations by using the FUCCI reporter system in human pluripotent stem cells and show that their capacity of differentiation varies during the progression of their cell cycle. These mechanisms are governed by the cell-cycle regulators cyclin D1–3 that control differentiation signals such as the TGF-β-Smad2/3 pathway. Conversely, cell-cycle manipulation using a small molecule directs differentiation of hPSCs and provides an approach to generate cell types with a clinical interest. Our results demonstrate that cell fate decisions are tightly associated with the cell-cycle machinery and reveal insights in the mechanisms synchronizing differentiation and proliferation in developing tissues. Cell fate decisions are cell-cycle dependent Control of endoderm versus neuroectoderm differentiation by cyclin D-CDK4/6 Cyclin Ds control TGF-β-Smad2/3 transcriptional activity Differentiation of hPSCs can be directed by manipulation of the cell cycle Cell fate decisions are influenced by the cell-cycle state and cyclin D activity of a stem cell as it embarks on differentiation. Cyclin D acts via TGF-β-Smad signaling to alter the propensity for endoderm versus neuroectoderm fate.
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影响因子：
64.5
作者：
Mullen AC;Orlando DA;Newman JJ;Lovén J;Kumar RM;Bilodeau S;Reddy J;Guenther MG;DeKoter RP;Young RA
通讯作者：
Young RA
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
DOI：
10.1126/science.1180794
发表时间：
2010-01-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li L;Clevers H
通讯作者：
Clevers H
影响因子：
64.5
作者：
Sakaue-Sawano, Asako;Kurokawa, Hiroshi;Miyawaki, Atsushi
通讯作者：
Miyawaki, Atsushi
影响因子：
4
作者：
Calder, Ashley;Roth-Albin, Ivana;Draper, Jonathan S.
通讯作者：
Draper, Jonathan S.