Extraembryonic gut endoderm cells undergo programmed cell death during development (source data and custom code)

Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.尽管小鼠的胚外细胞（extraembryonic cells）具有独特的发育起源，但其可参与肠内胚层的形成，并在转录水平上逐渐与其胚胎来源的同类细胞趋于一致。值得注意的是，胚外祖细胞具有非经典表观基因组（non-canonical epigenome），这引发了一系列关键科学问题：该表观基因组图谱是否会被重置以匹配胚胎的调控模式，以及这类细胞是否会持续存在至发育后期。本研究开发了一种双色谱系示踪技术（two-color lineage tracing strategy），可随时间推移对胚外细胞进行追踪与分离。研究发现，胚外肠细胞保留了其发育起源的显著记忆，包括原始DNA甲基化图谱（DNA methylation landscape）以及由此产生的转录特征的留存。此外，本研究证实胚外肠细胞会发生程序性细胞死亡（programmed cell death），而邻近的胚胎细胞可通过非专业吞噬作用（non-professional phagocytosis）清除其残骸。在胚胎发育中期，野生型（wild type）小鼠肠道中已无法检测到胚外细胞；而在p53突变胚胎（p53 mutant embryos）中，这类细胞仍可持续存在并进一步分化。本研究为胚胎内的胚外细胞的分子特征与发育命运提供了关键见解。