In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion.

中文翻译：

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TNFSF14+ 自然杀伤细胞通过限制亮氨酸介导的蜕膜基质细胞衰老来防止自然流产。


为了准备潜在的怀孕，子宫的子宫内膜会变成一个称为蜕膜的临时结构。衰老的蜕膜基质细胞 （DSCs） 在蜕膜化过程中富集在蜕膜中，但这一过程的潜在机制仍不清楚。在这里，我们对 ESC 和 DSC 进行了单细胞 RNA 转录组学，发现蜕膜化过程中的细胞衰老伴随着支链氨基酸 （BCAA） 转运蛋白 SLC3A2 水平的增加。从培养基中去除亮氨酸（支链氨基酸之一）可减缓衰老，而高亮氨酸饮食导致小鼠衰老增加和胚胎丢失率高。BCAA 通过 p38 MAPK 通路诱导 DSC 衰老。相比之下，发现 TNFSF14 + 蜕膜自然杀伤 （dNK） 细胞通过与配体TNFRSF14相互作用来抑制 DSC 衰老。与饲喂高亮氨酸饮食的小鼠一样，NK 细胞耗竭的小鼠和子宫过度衰老的 Tnfrsf14 缺陷小鼠都经历了不良的妊娠结局。此外，我们发现复发性自然流产患者的子宫过度衰老、SLC3A2 介导的 BCAA 摄入和 TNFRSF14 表达不足。总之，本研究提示 dNK 细胞通过 TNFSF14/TNFRSF14 维持 DSC 的衰老稳态，为预防 DSC 衰老相关自然流产提供了一种潜在的治疗策略。