人胎盘间充质干细胞来源的外泌体转运来自妊娠期糖尿病患者的 microRNA-130b-3p，靶向 ICAM-1，扰乱人脐静脉内皮细胞血管生成。
Human placenta mesenchymal stem cell-derived exosome shuttling microRNA-130b-3p from gestational diabetes mellitus patients targets ICAM-1 and perturbs human umbilical vein endothelial cell angiogenesis.
机构信息
Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China.
出版信息
Acta Diabetol. 2022 Aug;59(8):1091-1107. doi: 10.1007/s00592-022-01910-2. Epub 2022 Jun 8.
OBJECTIVE
The aim of this study was to investigate the roles of miR-130b-3p and ICAM-1 in gestational diabetes mellitus (GDM) and their potential association.
METHODS
Human placenta mesenchymal stem cells (PlaMSCs) were isolated from GDM patients, and the effects of the PlaMSCs from GDM patients (GDM-MSCs) and the exosomes secreted by GDM-MSCs on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and angiogenesis were detected. Next, GDM-MSCs were transfected with miR-130b-3p antagomir to modify miR-130b-3p expression in GDM-MSCs-derived exosomes, and the exosomes with modified miR-130b-3p expression were cultured with HUVECs to evaluate exosomal miR-130b-3p on HUVEC function. Furthermore, a target gene of miR-130b-3p was predicted and assessed. The miR-130b-3p-modified exosomes were cultured with HUVECs transfected with ICAM-1 shRNA to determine the effect of miR-130b-3p-ICAM-1 crosstalk on HUVEC function. Additionally, a GDM mouse model was conducted to further study the effect of miR-130b-3p in GDM in vivo.
RESULTS
GDM-MSCs inhibited HUVEC proliferation and angiogenesis. The elevated expression of miR-130b-3p was found in GDM-MSCs-derived exosomes. GDM-MSCs-derived exosomes repressed the proliferation and angiogenesis of HUVECs and miR-130b-3p inhibition could restrain the inhibition of the exosomes on HUVEC function. Mechanistically, miR-130b-3p downregulated ICAM-1 expression in a targeted manner, and thereby enhanced HUVEC proliferation, migration, and angiogenesis and increased the expression of angiogenesis-related factors. Moreover, miR-130b-3p inhibition promoted placental angiogenesis in GDM mice and upregulated ICAM-1 expression.
CONCLUSION
Conclusively, GDM-MSCs-derived exosomes shuttling miR-130b-3p repressed proliferation, migration, and angiogenesis of HUVECs by regulating ICAM-1 expression.
目的
本研究旨在探讨 miR-130b-3p 和 ICAM-1 在妊娠期糖尿病（GDM）中的作用及其潜在关联。
方法
从 GDM 患者中分离胎盘间充质干细胞（PlaMSCs），检测 GDM 患者来源的 PlaMSCs（GDM-MSCs）及其分泌的外泌体对人脐静脉内皮细胞（HUVEC）增殖、迁移和血管生成的影响。然后，用 miR-130b-3p 反义寡核苷酸转染 GDM-MSCs，修饰 GDM-MSCs 来源的外泌体中的 miR-130b-3p 表达，将修饰后的 miR-130b-3p 表达的外泌体与 HUVEC 共培养，评估外泌体 miR-130b-3p 对 HUVEC 功能的影响。进一步预测和评估 miR-130b-3p 的靶基因。将 miR-130b-3p 修饰的外泌体与转染了 ICAM-1 shRNA 的 HUVEC 共培养，以确定 miR-130b-3p-ICAM-1 相互作用对 HUVEC 功能的影响。此外，还进行了 GDM 小鼠模型实验，以进一步研究 miR-130b-3p 在体内 GDM 中的作用。
结果
GDM-MSCs 抑制 HUVEC 增殖和血管生成。在 GDM-MSCs 来源的外泌体中发现 miR-130b-3p 表达升高。GDM-MSCs 来源的外泌体抑制 HUVEC 的增殖和血管生成，抑制外泌体对 HUVEC 功能的抑制作用。机制上，miR-130b-3p 以靶向方式下调 ICAM-1 的表达，从而增强 HUVEC 的增殖、迁移和血管生成，并增加血管生成相关因子的表达。此外，miR-130b-3p 抑制促进 GDM 小鼠胎盘血管生成，并上调 ICAM-1 表达。
结论
综上所述，GDM-MSCs 来源的外泌体通过调节 ICAM-1 的表达，抑制 HUVEC 的增殖、迁移和血管生成。
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