The cleavage of zygotes generates totipotent blastomeres. In human 8-cell blastomeres, zygotic genome activation (ZGA) occurs to initiate the ontogenesis program. However, capturing and maintaining totipotency in human cells pose significant challenges. Here, we realize culturing human totipotent blastomere-like cells (hTBLCs). We find that splicing inhibition can transiently reprogram human pluripotent stem cells into ZGA-like cells (ZLCs), which subsequently transition into stable hTBLCs after long-term passaging. Distinct from reported 8-cell-like cells (8CLCs), both ZLCs and hTBLCs widely silence pluripotent genes. Interestingly, ZLCs activate a particular group of ZGA-specific genes, and hTBLCs are enriched with pre-ZGA-specific genes. During spontaneous differentiation, hTBLCs re-enter the intermediate ZLC stage and further generate epiblast (EPI)-, primitive endoderm (PrE)-, and trophectoderm (TE)-like lineages, effectively recapitulating human pre-implantation development. Possessing both embryonic and extraembryonic developmental potency, hTBLCs can autonomously generate blastocyst-like structures without external cell signaling. In summary, our study provides key criteria and insights into human cell totipotency.

中文翻译：

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通过剪接体抑制捕获人类细胞的全能性


受精卵的分裂产生全能卵裂球。在人类 8 细胞卵裂球中，合子基因组激活 (ZGA) 发生以启动个体发生程序。然而，捕获和维持人类细胞的全能性提出了重大挑战。在这里，我们实现了人全能卵裂球样细胞（hTBLC）的培养。我们发现剪接抑制可以将人类多能干细胞瞬时重编程为ZGA样细胞（ZLC），随后在长期传代后转变为稳定的hTBLC。与报道的 8 细胞样细胞 (8CLC) 不同，ZLC 和 hTBLC 都广泛沉默多能基因。有趣的是，ZLC 激活一组特定的 ZGA 特异性基因，而 hTBLC 富含前 ZGA 特异性基因。在自发分化过程中，hTBLC 重新进入中间 ZLC 阶段，并进一步生成外胚层 (EPI)、原始内胚层 (PrE) 和滋养外胚层 (TE) 样谱系，有效地再现了人类植入前发育。 hTBLC 具有胚胎和胚胎外发育能力，无需外部细胞信号传导即可自主生成囊胚样结构。总之，我们的研究提供了人类细胞全能性的关键标准和见解。