Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation.
Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation.
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DOI：
10.1016/j.devcel.2013.06.012
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发表时间：
2013-07-15
影响因子：
11.8
通讯作者：
Rodriguez, Tristan A.
中科院分区：
文献类型：
--
作者：
Sancho, Margarida;Di-Gregorio, Aida;George, Nancy;Pozzi, Sara;Sanchez, Juan Miguel;Pernaute, Barbara;Rodriguez, Tristan A.
发育生物学中的一个基本问题是，是否有机制检测带有突变的干细胞，这些突变虽然不会对生存能力产生不利影响，但会损害它们促进进一步发育的能力。在这里，我们表明细胞竞争是一种调节胚胎干细胞(ESCs)适合性的机制。我们发现，显示骨形态发生蛋白信号缺陷或自噬缺陷或四倍体的胚胎干细胞在分化开始时被野生型细胞消除。这种消除是以一种依赖于细胞凋亡的方式发生的，并由分泌因子介导。此外，在这个过程中，我们发现建立不同的c-Myc水平是至关重要的，c-Myc的过度表达足以诱导ESCs的竞争行为。因此，细胞竞争是一个过程，允许在发育的早期阶段识别和消除有缺陷的细胞，并可能在组织稳态和干细胞维持中发挥重要作用。野生型胚胎干细胞在分化初期被野生型细胞消除，不适合细胞的消除依赖于细胞的凋亡和分泌因子的调节，野生型胚胎干细胞在与不适合细胞共培养时c-Myc水平升高，c-Myc过表达诱导胚胎干细胞在Sancho等人中具有竞争优势。表明胚胎干细胞在分化开始时会经历细胞竞争来识别和消除有缺陷的邻居。在哺乳动物早期胚胎发育过程中，由c-Myc差异表达驱动的细胞竞争为监测多能干细胞的适合性提供了一种机制。
A fundamental question in developmental biology is whether there are mechanisms to detect stem cells with mutations that, although not adversely affecting viability, would compromise their ability to contribute to further development. Here, we show that cell competition is a mechanism regulating the fitness of embryonic stem cells (ESCs). We find that ESCs displaying defective bone morphogenetic protein signaling or defective autophagy or that are tetraploid are eliminated at the onset of differentiation by wild-type cells. This elimination occurs in an apoptosis-dependent manner and is mediated by secreted factors. Furthermore, during this process, we find that establishment of differential c-Myc levels is critical and that c-Myc overexpression is sufficient to induce competitive behavior in ESCs. Cell competition is, therefore, a process that allows recognition and elimination of defective cells during the early stages of development and is likely to play important roles in tissue homeostasis and stem cell maintenance. Defective ESCs are eliminated at the onset of differentiation by wild-type cells Elimination of unfit cells is apoptosis dependent and mediated by secreted factors Higher c-Myc levels are established in wild-type ESCs cocultured with unfit cells c-Myc overexpression induces a competitive advantage in ESCs Sancho et al. show that embryonic stem cells undergo cell competition to recognize and eliminate defective neighbors at the onset of differentiation. Cell competition, driven by differential c-Myc expression, provides a mechanism to monitor the fitness of pluripotent stem cells during early mammalian embryogenesis.
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