Laboratory of Embryonic Stem Cell Research, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8351, Japan.
Stem Cell Reports. 2020 Mar 10;14(3):506-519. doi: 10.1016/j.stemcr.2020.01.012. Epub 2020 Feb 20.
Naive and primed human pluripotent stem cells (hPSCs) have provided useful insights into the regulation of pluripotency. However, the molecular mechanisms regulating naive conversion remain elusive. Here, we report intermediate naive conversion induced by overexpressing nuclear receptor 5A1 (NR5A1) in hPSCs. The cells displayed some naive features, such as clonogenicity, glycogen synthase kinase 3β, and mitogen-activated protein kinase (MAPK) independence, expression of naive-associated genes, and two activated X chromosomes, but lacked others, such as KLF17 expression, transforming growth factor β independence, and imprinted gene demethylation. Notably, NR5A1 negated MAPK activation by fibroblast growth factor 2, leading to cell-autonomous self-renewal independent of MAPK inhibition. These phenotypes may be associated with naive conversion, and were regulated by a DPPA2/4-dependent pathway that activates the selective expression of naive-associated genes. This study increases our understanding of the mechanisms regulating the conversion from primed to naive pluripotency.
幼稚态和起始态的人类多能干细胞（hPSCs）为多能性调控提供了有用的见解。然而，调节起始态转换的分子机制仍难以捉摸。在这里，我们报告了通过在 hPSCs 中转染核受体 5A1（NR5A1）来诱导中间起始态转换。这些细胞表现出一些起始态特征，如克隆形成能力、糖原合酶激酶 3β 和丝裂原激活蛋白激酶（MAPK）独立性、起始态相关基因的表达和两个激活的 X 染色体，但缺乏其他特征，如 KLF17 表达、转化生长因子 β 独立性和印记基因去甲基化。值得注意的是，NR5A1 可否定 MAPK 由成纤维细胞生长因子 2 激活，导致细胞自主的自我更新，而不依赖于 MAPK 抑制。这些表型可能与起始态转换有关，并受到 DPPA2/4 依赖性途径的调节，该途径激活了起始态相关基因的选择性表达。这项研究增加了我们对调节从起始态到幼稚态多能性转换的机制的理解。
