蜕膜基质细胞衍生的外泌体通过靶向 PDK4 将 miR-22-5p_R-1 递送至滋养细胞，从而抑制不明原因复发性自然流产中滋养细胞从线粒体呼吸到糖酵解的代谢转换。

Decidual stromal cell-derived exosomes deliver miR-22-5p_R-1 to suppress trophoblast metabolic switching from mitochondrial respiration to glycolysis by targeting PDK4 in unexplained recurrent spontaneous abortion.

机构信息

Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China; Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

出版信息

Placenta. 2024 Aug;153:1-21. doi: 10.1016/j.placenta.2024.05.131. Epub 2024 May 23.

DOI:10.1016/j.placenta.2024.05.131

PMID:38810540

Abstract

INTRODUCTION

Studies have shown that EMT (epithelial-mesenchymal transition) and energy metabolism influence each other, and it is unclear whether the trophoblast energy metabolism phenotype is dominated by glycolysis or mitochondrial respiration, and the relationship between trophoblast energy metabolism and EMT is still unclear.

METHODS

Exosomes were isolated from the DSC of URSA patients and their miRNA profile was characterized by miRNA sequencing. Wound healing assays and transwell assays were used to assess the invasion and migration ability of trophoblasts. Mitochondrial stress and glycolysis stress test were used to evaluate energy metabolism phenotype of trophoblast. Luciferase reporter assays, qRT-PCR and WB were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of DSC-exos on embryo absorption in mice.

RESULTS

Our results showed that URSA-DSC-exos suppressed trophoblast EMT to reduce their migration and invasion, miR-22-5p_R-1 was the most upregulated miRNAs. URSA-DSC-exos can suppress trophoblast MGS (metabolic switch from mitochondrial respiration to glycolysis) and inhibit trophoblast migration and invasion by transferring miR-22-5p_R-1. Mechanistically, miR-22-5p_R-1 suppress trophoblast MGS and inhibit trophoblast EMT by directly suppressing PDK4 expression at the post-transcriptional level. Furthermore, in vivo experiment suggested that URSA-DSC-exos aggravated embryo absorption in mice. Clinically, PDK4 and EMT molecule were aberrant in villous of URSA patients, and negative correlations were found between miR-22-5p_R-1 and PDK4.

DISCUSSION

Our findings indicated that URSA-DSC-exos induced MGS obstacle playing an important role in intercellular communication between trophoblast and DSC, illuminating a novel mechanism in DSC regulation of trophoblasts and their role in URSA.

摘要

简介

研究表明 EMT（上皮-间质转化）和能量代谢相互影响，尚不清楚滋养细胞的能量代谢表型是由糖酵解还是线粒体呼吸主导，滋养细胞能量代谢与 EMT 的关系尚不清楚。

方法

从 URSA 患者的 DSC 中分离外泌体，并通过 miRNA 测序对其 miRNA 谱进行特征分析。划痕愈合试验和 Transwell 试验用于评估滋养细胞的侵袭和迁移能力。线粒体应激和糖酵解应激试验用于评估滋养细胞的能量代谢表型。荧光素酶报告基因检测、qRT-PCR 和 WB 用于揭示潜在的机制。最后，动物实验用于研究 DSC-exos 在小鼠中对胚胎吸收的影响。

结果

我们的结果表明，URSA-DSC-exos 抑制滋养细胞 EMT 以降低其迁移和侵袭能力，miR-22-5p_R-1 是上调最明显的 miRNA。URSA-DSC-exos 可以通过转移 miR-22-5p_R-1 来抑制滋养细胞 MGS（从线粒体呼吸到糖酵解的代谢转换）并抑制滋养细胞迁移和侵袭。在机制上，miR-22-5p_R-1 通过直接在转录后水平抑制 PDK4 的表达来抑制滋养细胞 MGS 和 EMT。此外，体内实验表明，URSA-DSC-exos 加重了小鼠胚胎吸收。临床上，URSA 患者绒毛中 PDK4 和 EMT 分子异常，miR-22-5p_R-1 与 PDK4 呈负相关。