SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate. Homo sapiens

Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information. Overall design: RNA-Seq analysis to investigate transcriptomes of hPGC-like cells (hPGCLCs), fetal hPGCs, TCam-2 and hESCs

原始生殖细胞（primordial germ cells, PGCs）的特化标志着全能性状态的起始。然而，由于缺乏可操作的实验模型，人类原始生殖细胞（human PGC, hPGC）的特化机制至今仍未明确。本研究证实，可从生殖系兼容多能干细胞中诱导获得人类原始生殖细胞样细胞（human PGC-like cells, hPGCLCs）。该细胞的特征与胚胎期人类原始生殖细胞及表达CD38细胞表面标志物的生殖系精原细胞瘤相一致，上述三类样本共同界定了早期人类生殖系的潜在发育进程。值得注意的是，SOX17是调控人类原始生殖细胞样细胞命运的关键因子，而BLIMP1在人类原始生殖细胞样细胞特化过程中可抑制内胚层及其他体细胞基因的表达。小鼠与人类原始生殖细胞特化过程中存在显著的机制差异，这一差异或源于二者迥异的胚胎发育模式与多能性状态，且可能影响其他早期细胞命运决定事件。本研究为后续探究人类原始生殖细胞样细胞及人类原始生殖细胞的表观基因组重编程（以实现全能性及遗传与表观遗传信息的传递）奠定了重要研究基础。整体实验设计：通过RNA测序（RNA-Seq）分析人类原始生殖细胞样细胞、胎儿期人类原始生殖细胞、TCam-2细胞系及人类胚胎干细胞（human embryonic stem cells, hESCs）的转录组。