Reprogramming primordial germ cells into pluripotent stem cells.
Reprogramming primordial germ cells into pluripotent stem cells.
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DOI：
10.1371/journal.pone.0003531
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Surani MA
中科院分区：
文献类型：
--
作者：
Durcova-Hills G;Tang F;Doody G;Tooze R;Surani MA
原始生殖细胞(PGCs)的特化导致多能上皮细胞向单性生殖细胞谱系的转化。Blimp1/PRMT5复合体在早期生殖细胞谱系的确定和维持中起着关键作用。然而，在外源性信号分子成纤维细胞生长因子-2、激光诱导因子和干细胞因子的作用下，PGCs可以被诱导去分化回多能状态，成为胚胎生殖细胞。在此，我们证明了组蛋白脱乙酰酶抑制剂曲古抑素A(TSA)是一种高效的药物，可以取代成纤维细胞生长因子-2来诱导PGCs脱分化为EG细胞。在PGCs对成纤维细胞生长因子-2或TSA的反应中，一个关键的早期事件是Blimp1的下调，它逆转并明显解除了由它施加的细胞命运限制。值得注意的是，Blimp1的靶点上调，其中包括c-Myc和KLF-4，这是已知的促进体细胞重新编程到多能性状态的两个关键因素。我们还发现，随着Stat-3移位到细胞核中，LIF/Stat-3信号通路被早期激活。相比之下，虽然PRMT5保留在EG细胞中，但它从细胞核转移到细胞质，在那里它可能在调节多能性方面具有独立的作用。我们认为，将PGCs去分化为EG细胞可能为与承诺细胞重新编程为多能状态相关的早期事件提供重要的机械性见解。
Specification of primordial germ cells (PGCs) results in the conversion of pluripotent epiblast cells into monopotent germ cell lineage. Blimp1/Prmt5 complex plays a critical role in the specification and maintenance of the early germ cell lineage. However, PGCs can be induced to dedifferentiate back to a pluripotent state as embryonic germ (EG) cells when exposed to exogenous signaling molecules, FGF-2, LIF and SCF. Here we show that Trichostatin A (TSA), an inhibitor of histone deacetylases, is a highly potent agent that can replace FGF-2 to induce dedifferentiation of PGCs into EG cells. A key early event during dedifferentiation of PGCs in response to FGF-2 or TSA is the down-regulation of Blimp1, which reverses and apparently relieves the cell fate restriction imposed by it. Notably, the targets of Blimp1, which include c-Myc and Klf-4, which represent two of the key factors known to promote reprogramming of somatic cells to pluripotent state, are up-regulated. We also found early activation of the LIF/Stat-3 signaling pathway with the translocation of Stat-3 into the nucleus. By contrast, while Prmt5 is retained in EG cells, it translocates from the nucleus to the cytoplasm where it probably has an independent role in regulating pluripotency. We propose that dedifferentiation of PGCs into EG cells may provide significant mechanistic insights on early events associated with reprogramming of committed cells to a pluripotent state.
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