Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

中文翻译：

---

模拟蜕膜衰老对人类子宫内膜组合体胚胎植入的影响


黄体中期子宫内膜的蜕膜重塑会导致较短的植入窗口，此后子宫粘膜要么分解，要么转化为坚固的基质，在整个怀孕期间容纳胎盘。为了深入了解潜在机制，我们建立并表征了子宫内膜组合体，由腺样类器官和原代基质细胞组成。单细胞转录组学显示，蜕膜化组合体与黄体中期子宫内膜非常相似，在腺体和间质中都含有分化和衰老的亚群。我们发现，腺上皮的急性衰老驱动多种经典植入因子的分泌，而在基质中，它校准抗炎蜕膜细胞和促炎衰老蜕膜细胞的出现。对蜕膜前细胞应激反应的药理学抑制通过消除衰老蜕膜细胞的出现来加速蜕膜化。在共培养实验中，加速的蜕膜化导致塌陷的人类囊胚被困在坚固的静态蜕膜基质中。相比之下，衰老蜕膜细胞的存在创造了一个动态的植入环境，使胚胎能够扩张和附着，尽管它们的持续存在导致组合体逐渐解体。我们的研究结果表明，蜕膜衰老控制着床时子宫内膜的命运决定，并强调子宫内膜组合体如何加速发现新的治疗方法以预防生殖失败。