Derivation of trophoblast stem cells from naïve human pluripotent stem cells [RNA-seq]

Naïve human pluripotent stem cells (hPSCs) provide a unique experimental platform of cell fate decisions during pre-implantation development, but their lineage potential remains incompletely characterized. As naïve hPSCs share transcriptional and epigenomic signatures with trophoblast cells, it has been proposed that the naïve state may have enhanced predisposition for differentiation along this extraembryonic lineage. Here we examined the trophoblast potential of isogenic naïve and primed hPSCs. We found that naïve hPSCs can directly give rise to human trophoblast stem cells (hTSCs) and undergo further differentiation into both extravillous and syncytiotrophoblast. In contrast, primed hPSCs do not support hTSC derivation, but give rise to non-self-renewing cytotrophoblasts in response to BMP4. Global transcriptome and chromatin accessibility analyses indicate that hTSCs derived from naïve hPSCs acquire features of pre-implantation trophectoderm. The derivation of hTSCs from naïve hPSCs will enable elucidation of early mechanisms that govern normal human trophoblast development and associated pathologies. Overall design: Bulk RNA-seq of seven cell types

初始态人类多能干细胞（naïve human pluripotent stem cells, hPSCs）为植入前发育过程中的细胞命运决定提供了独特的实验平台，但其谱系分化潜能仍未被完全阐明。由于初始态hPSCs与滋养层细胞共享转录组与表观基因组特征，有研究提出初始态可能更倾向于向该胚外谱系分化。本研究针对同基因背景下初始态与primed态人类多能干细胞（primed hPSCs）的滋养层分化潜能展开探究。我们发现，初始态hPSCs可直接分化为人类滋养层干细胞（human trophoblast stem cells, hTSCs），并可进一步分化为绒毛外滋养层细胞与合体滋养层细胞。与之相反，primed态hPSCs无法支持hTSCs的诱导生成，但在骨形态发生蛋白4（bone morphogenetic protein 4, BMP4）的诱导下可分化为无法自我更新的细胞滋养层细胞。全局转录组与染色质可及性分析显示，由初始态hPSCs诱导得到的hTSCs具备植入前滋养外胚层的特征。通过初始态hPSCs诱导生成hTSCs的方法，将有助于阐明调控正常人类滋养层发育及相关病理过程的早期分子机制。实验设计：对7种细胞类型进行批量RNA测序（bulk RNA-seq）。