Interspecies blastocyst complementation enables organ-specific enrichment of xenogeneic pluripotent stem cell (PSC) derivatives, which raises an intriguing possibility to generate functional human tissues/organs in an animal host. However, differences in embryo development between human and host species may constitute the barrier for efficient chimera formation. Here, to understand these differences we constructed a complete single-cell landscape of early embryonic development of pig, which is considered one of the best host species for human organ generation, and systematically compared its epiblast development with that of human and monkey. Our results identified a developmental coordinate of pluripotency spectrum among pigs, humans and monkeys, and revealed species-specific differences in: (1) pluripotency progression; (2) metabolic transition; (3) epigenetic and transcriptional regulations of pluripotency; (4) cell surface proteins; and (5) trophectoderm development. These differences may prevent proper recognition and communication between donor human cells and host pig embryos, resulting in low integration and survival of human cells. These results offer new insights into evolutionary conserved and divergent processes during mammalian development and may be helpful for developing effective strategies to overcome low human–pig chimerism, thereby enabling the generation of functional human organs in pigs in the future.

种间囊胚互补使异种多能干细胞 (PSC) 衍生物的器官特异性富集成为可能，这为在动物宿主中产生功能性人体组织/器官提供了一种有趣的可能性。然而，人类和宿主物种之间胚胎发育的差异可能构成有效形成嵌合体的障碍。在这里，为了理解这些差异，我们构建了猪早期胚胎发育的完整单细胞景观，猪被认为是人类器官生成的最佳宿主物种之一，并系统地将其外胚层发育与人类和猴子的外胚层发育进行了比较。我们的结果确定了猪、人类和猴子之间多能性谱的发育坐标，并揭示了以下方面的物种特异性差异：（1）多能性进展；(2)代谢转变；(3) 多能性的表观遗传和转录调控；(4)细胞表面蛋白；(5) 滋养外胚层发育。这些差异可能会阻碍供体人类细胞和宿主猪胚胎之间的正确识别和交流，导致人类细胞的整合和存活率低。这些结果提供了对哺乳动物发育过程中进化保守和发散过程的新见解，并可能有助于制定有效的策略来克服低人猪嵌合现象，从而在未来在猪身上产生功能性人体器官。导致人类细胞的低整合和存活。这些结果提供了对哺乳动物发育过程中进化保守和发散过程的新见解，并可能有助于制定有效的策略来克服低人猪嵌合现象，从而在未来在猪身上产生功能性人体器官。导致人类细胞的低整合和存活。这些结果提供了对哺乳动物发育过程中进化保守和发散过程的新见解，并可能有助于制定有效的策略来克服低人猪嵌合现象，从而在未来在猪身上产生功能性人体器官。