Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.

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.

黄体中期子宫内膜的蜕膜重塑会形成短暂的植入窗，此后子宫黏膜要么发生降解，要么转化为可在整个妊娠期间容纳胎盘的坚固基质。为深入探究其潜在机制，我们构建并表征了由腺类器官与原代基质细胞组成的子宫内膜类组装体（endometrial assembloids）。单细胞转录组学分析显示，蜕膜化的子宫内膜类组装体与黄体中期子宫内膜高度相似，在腺体和基质中均存在分化亚群与衰老亚群。我们证实，腺上皮的急性衰老可驱动多种经典植入因子的分泌；而在基质中，衰老现象可调控抗炎型蜕膜细胞与促炎型衰老蜕膜细胞的产生。对蜕膜前体细胞的应激反应进行药物抑制，可通过消除衰老蜕膜细胞的产生来加速蜕膜化过程。共培养实验表明，加速的蜕膜化会使塌陷的人囊胚被困于坚固且静态的蜕膜基质中。与之相反，衰老蜕膜细胞的存在会营造出动态的植入环境，支持胚胎扩增与附着，但其持续存在会导致子宫内膜类组装体逐渐解体。我们的研究结果表明，蜕膜衰老可调控植入阶段子宫内膜的命运抉择，并凸显了子宫内膜类组装体可如何加速新型防治生殖失败疗法的开发。