State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute of Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China.
National Clinical Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
Genomics Proteomics Bioinformatics. 2021 Apr;19(2):208-222. doi: 10.1016/j.gpb.2020.11.002. Epub 2021 Jan 19.
Successful pregnancy in placental mammals substantially depends on the establishment of maternal immune tolerance to the semi-allogenic fetus. Disorders in this process are tightly associated with adverse pregnancy outcomes including recurrent miscarriage (RM). However, an in-depth understanding of the systematic and decidual immune environment in RM remains largely lacking. In this study, we utilized single-cell RNA-sequencing (scRNA-seq) to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and unexplained RM pregnancies at the early stage of gestation. Integrative analysis identifies 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RM cases is revealed. Specifically, the cytotoxic properties of CD8 effector T cells, nature killer (NK), and mucosal-associated invariant T (MAIT) cells in peripheral blood indicates apparently enhanced pro-inflammatory status, and the population proportions and ligand-receptor interactions of the decidual leukocyte subsets demonstrate preferential immune activation in RM patients. The molecular features, spatial distribution, and the developmental trajectories of five decidual NK (dNK) subsets have been elaborately illustrated. In RM patients, a dNK subset that supports embryonic growth is diminished in proportion, while the ratio of another dNK subset with cytotoxic and immune-active signature is significantly increased. Notably, a unique pro-inflammatory CD56CD16 dNK subset substantially accumulates in RM decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy and provide an in-depth insight into the immune pathogenesis for early pregnancy loss.
成功妊娠在胎盘哺乳动物中在很大程度上取决于母体对半同种异体胎儿建立免疫耐受。这一过程中的紊乱与包括复发性流产（RM）在内的不良妊娠结局密切相关。然而，对 RM 中系统性和蜕膜免疫环境的深入了解在很大程度上仍然缺乏。在这项研究中，我们利用单细胞 RNA 测序（scRNA-seq）比较分析了正常妊娠和不明原因 RM 妊娠早期蜕膜和外周白细胞的细胞和分子特征。整合分析总共鉴定出 22 个不同的细胞簇，揭示了 RM 病例中外周血白细胞亚群和分子特性的显著差异。具体而言，外周血中 CD8 效应 T 细胞、自然杀伤（NK）和黏膜相关不变 T（MAIT）细胞的细胞毒性特性表明明显增强的促炎状态，而蜕膜白细胞亚群的群体比例和配体-受体相互作用表明 RM 患者优先免疫激活。详细阐述了五个蜕膜 NK（dNK）亚群的分子特征、空间分布和发育轨迹。在 RM 患者中，支持胚胎生长的 dNK 亚群比例降低，而具有细胞毒性和免疫活性特征的另一个 dNK 亚群的比例显著增加。值得注意的是，一种独特的促炎 CD56CD16 dNK 亚群在 RM 蜕膜中大量积累。这些发现揭示了人类早期妊娠中蜕膜和外周白细胞的全面细胞和分子图谱，并深入了解了早期妊娠丢失的免疫发病机制。
