Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Obstetrics and Gynaecology, Monash Health, Monash University, Victoria, Australia.
Mol Hum Reprod. 2021 Sep 29;27(10). doi: 10.1093/molehr/gaab057.
Adequate endometrial stromal cell (ESC) decidualization is vital for endometrial health. Given the importance of extracellular vesicles (EVs) in intercellular communication, we investigated how their protein landscape is reprogrammed and dysregulated during decidual response. Small EVs (sEVs) from human ESC-conditioned media at Day-2 and -14 following decidual stimuli were grouped as well- (WD) or poorly decidualized (PD) based on their prolactin secretion and subjected to mass spectrometry-based quantitative proteomics. On Day 2, in PD- versus WD-ESC-sEVs, 17 sEV- proteins were down-regulated (C5, C6; complement/coagulation cascades, and SERPING1, HRG; platelet degranulation and fibrinolysis) and 39 up-regulated (FLNA, COL1A1; focal adhesion, ENO1, PKM; glycolysis/gluconeogenesis, and RAP1B, MSN; leukocyte transendothelial migration). On Day 14, in PD- versus WD-ESC-sEVs, FLNA was down-regulated while 21 proteins were up-regulated involved in complement/coagulation cascades (C3, C6), platelet degranulation (SERPINA4, ITIH4), B-cell receptor signalling and innate immune response (immunoglobulins). Changes from Days 2 to 14 suggested a subsequent response in PD-ESC-sEVs with 89 differentially expressed proteins mostly involved in complement and coagulation cascades (C3, C6, C5), but no change in WD-ESC-sEVs ESC. Poor decidualization was also associated with loss of crucial sEV-proteins for cell adhesion and invasion (ITGA5, PFN1), glycolysis (ALDOA, PGK1) and cytoskeletal reorganization (VCL, RAC1). Overall, this study indicates varied ESC response even prior to decidualization and provides insight into sEVs-proteomes as a benchmark of well-decidualized ESC. It shows distinct variation in sEV-protein composition depending on the ESC decidual response that is critical for embryo implantation, enabling and limiting trophoblast invasion during placentation and sensing a healthy embryo.
足够的子宫内膜基质细胞（ESC）蜕膜化对于子宫内膜健康至关重要。鉴于细胞外囊泡（EVs）在细胞间通讯中的重要性，我们研究了它们的蛋白质图谱在蜕膜反应过程中是如何被重新编程和失调的。根据其催乳素分泌情况，将人 ESC 条件培养基在蜕膜刺激后的第 2 天和第 14 天产生的小 EV（sEV）分为蜕膜化良好（WD）或蜕膜化不良（PD）组，并进行基于质谱的定量蛋白质组学分析。在第 2 天，与 WD-ESC-sEV 相比，PD-ESC-sEV 中有 17 种 sEV 蛋白下调（C5、C6；补体/凝血级联和 SERPING1、HRG；血小板脱颗粒和纤维蛋白溶解），39 种 sEV 蛋白上调（FLNA、COL1A1；焦点粘附、ENO1、PKM；糖酵解/糖异生和 RAP1B、MSN；白细胞穿过内皮迁移）。在第 14 天，与 WD-ESC-sEV 相比，PD-ESC-sEV 中的 FLNA 下调，而 21 种蛋白上调，涉及补体/凝血级联（C3、C6）、血小板脱颗粒（SERPINA4、ITIH4）、B 细胞受体信号转导和固有免疫反应（免疫球蛋白）。从第 2 天到第 14 天的变化表明 PD-ESC-sEV 随后发生反应，有 89 种差异表达蛋白主要涉及补体和凝血级联（C3、C6、C5），而 WD-ESC-sEV 没有变化。蜕膜化不良还与丧失细胞粘附和入侵（ITGA5、PFN1）、糖酵解（ALDOA、PGK1）和细胞骨架重排（VCL、RAC1）所需的关键 sEV 蛋白有关。总的来说，这项研究表明，即使在蜕膜化之前，ESC 也会有不同的反应，并深入了解 sEV 蛋白组作为蜕膜化良好的 ESC 的基准。它显示了 sEV 蛋白组成的明显变化，这取决于 ESC 的蜕膜反应，这对于胚胎着床至关重要，使滋养层侵入胎盘，并感知健康的胚胎。
