College of Veterinary Medicine, Shaanxi Center of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Cell Death Dis. 2018 Feb 14;9(2):224. doi: 10.1038/s41419-018-0335-1.
Unipotent spermatogonial stem cells (SSCs) can be efficiently reprogrammed into pluripotent stem cells only by manipulating the culture condition, without introducing exogenous reprogramming factors. This phenotype raises the hypothesis that the endogenous transcription factors (TFs) in SSCs may facilitate reprogramming to acquire pluripotency. In this study, we screened a pool of SSCs TFs (Bcl6b, Lhx1, Foxo1, Plzf, Id4, Taf4b, and Etv5), and found that oncogene Etv5 could dramatically increase the efficiency of induced pluripotent stem cells (iPSCs) generation when combined with Yamanaka factors. We also demonstrated that Etv5 could promote mesenchymal-epithelial transition (MET) at the early stage of reprogramming by regulating Tet2-miR200s-Zeb1 axis. In addition, Etv5 knockdown in mouse embryonic stem cells (mESCs) could decrease the genomic 5hmC level by downregulating Tet2. Furthermore, the embryoid body assay revealed that Etv5 could positively regulate primitive endoderm specification through regulating Gata6 and negatively regulate epiblast specification by inhibiting Fgf5 expression. In summary, our findings provide insights into understanding the regulation mechanisms of Etv5 under the context of somatic reprogramming, mESCs maintenance, and differentiation.
单能精原干细胞（SSC）仅通过操纵培养条件就能有效地被重编程为多能干细胞，而无需引入外源性重编程因子。这种表型提出了一个假设，即 SSC 中的内源性转录因子（TFs）可能有助于重编程以获得多能性。在这项研究中，我们筛选了一组 SSCs TF（Bcl6b、Lhx1、Foxo1、Plzf、Id4、Taf4b 和 Etv5），并发现癌基因 Etv5 与 Yamanaka 因子结合时可以显著提高诱导多能干细胞（iPSC）的生成效率。我们还证明，Etv5 通过调节 Tet2-miR200s-Zeb1 轴在重编程的早期促进间充质上皮转化（MET）。此外，Etv5 在小鼠胚胎干细胞（mESC）中的敲低可以通过下调 Tet2 降低基因组 5hmC 水平。此外，胚状体测定表明，Etv5 可以通过调节 Gata6 正向调控原始内胚层的特化，通过抑制 Fgf5 表达负向调控外胚层的特化。总之，我们的研究结果为理解 Etv5 在体细胞重编程、mESC 维持和分化背景下的调控机制提供了新的见解。
