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.

天真和初免的人类多能干细胞（hPSC）为多能性的调节提供了有用的见识。但是，调节幼稚转化的分子机制仍然难以捉摸。在这里，我们报告由hPSCs中过表达核受体5A1（NR5A1）诱导的中间幼稚转化。这些细胞显示出一些天真的特征，例如克隆形成性，糖原合酶激酶3β和有丝分裂原激活的蛋白激酶（MAPK）独立性，天真相关基因的表达以及两个激活的X染色体，但缺乏其他特征，例如KLF17表达，转化生长因子β独立性和印迹基因去甲基化。值得注意的是，NR5A1否决了成纤维细胞生长因子2激活的MAPK，从而导致了独立于MAPK抑制的细胞自主自我更新。这些表型可能与幼稚的转化有关，并受到激活幼稚相关基因的选择性表达的DPPA2 / 4依赖性途径的调节。这项研究增加了我们对调节从启动多能性到幼稚多能性的机制的理解。