Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states.

Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states.

Embryonic stem cells (ESC) are apparently homogeneous self-renewing cells, but Stella, a marker of preimplantation embryos and germ cells showed heterogeneous expression in ESCs. Here we show that the Stella-positive ESCs were like the inner cell mass (ICM) while the Stella-negative cells were like the epiblast cells, although these populations exhibited interchangeability that reflected an adherence to an inherent program. Thus, ESCs are in a metastable state since they shift between the ICM- and epiblast-like phenotypes, which provides an insight into their instability, plasticity and pluripotency. This equilibrium was skewed reversibly by environmental and epigenetic cues; for example, the absence of signals from feeder cells caused a shift towards an epiblast-like state while trichostatin A, an inhibitor of histone deactelylase, restored Stella-positive population. Consistently, the two populations showed different histone modifications but with hypomethylated DNA in stella locus, as well as functional differences when induced to undergo differentiation. The Stella-negative cells were apparently more like the post-implantation epiblast-derived stem cells (EpiSCs), except that the stella locus was hypermethylated and repressed in the latter, which denotes a robust boundary between ESCs and EpiSCs.

胚胎干细胞（ESC）显然是均匀的自我更新细胞，但是Stella是植入前胚胎和生殖细胞的标记，在ESC中显示出异质的表达。在这里，我们表明Stella阳性ESC像内部细胞质量（ICM）一样，而Stella阴性细胞就像层细胞，尽管这些种群表现出互换性，反映了对固有程序的依从性。因此，ESC处于亚稳态状态，因为它们在ICM-和epiblast样表型之间转移，这提供了对其不稳定性，可塑性和多能性的见解。这种平衡是通过环境和表观遗传提示可逆的。例如，馈线细胞的缺失导致向层状状态转移，而trichostatin a（组蛋白的抑制剂deactelylase的抑制剂）恢复了Stella阳性群体。一致地，这两个种群显示出不同的组蛋白修饰，但在Stella基因座中具有低甲基化的DNA，并在引起分化时具有功能差异。 Stella阴性细胞显然更像是植入后培养细胞衍生的干细胞（EPISC），但斯特拉基因座在后者中被过度甲基化和抑制，这表示ESC和Episcs之间的强大边界。