Trophoblasts are extraembryonic cells that are essential for maintaining pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs), composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naive PSC-derived TE and CTs (nCTs) recreated human and monkey TE-to-CT transition. nCTs self-renewed as CT stem cells and had the characteristics of proliferating villous CTs and CTs in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (BMP4, A83-01, and PD173074 [BAP]-treated primed PSCs [pBAPs]), pBAPs were distinct from nCTs and human placenta-derived CT stem cells, exhibiting properties consistent with the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naive human PSCs. Our system provides a platform to study the molecular mechanisms underlying trophoblast development and related diseases.

滋养细胞是维持妊娠所必需的胚胎外细胞。人类滋养层细胞作为滋养外胚层 (TE) 来自桑椹胚，在植入后分化为细胞滋养层细胞 (CT)、合体滋养层 (ST) 和绒毛外滋养层 (EVT)，构成胎盘。在这里，我们展示了幼稚但未引发的人类多能干细胞 (PSC) 重述了滋养层发育。Naive PSC 衍生的 TE 和 CT (nCT) 重现了人类和猴子 TE 到 CT 的转变。nCTs自我更新为CT干细胞，具有增殖绒毛CTs和早孕期细胞柱CTs的特点。值得注意的是，虽然引发的 PSC 分化为滋养层样细胞（BMP4、A83-01 和 PD173074 [BAP] 处理的引发 PSC [pBAP]），但 pBAP 与 nCT 和人胎盘衍生的 CT 干细胞不同，表现出与羊膜一致的特性。我们的研究结果为人类滋养层发育建立了一个真实的范例，证明了幼稚人类 PSC 的宝贵特性。我们的系统提供了一个平台来研究滋养层发育和相关疾病的分子机制。