Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia.
Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
Clin Sci (Lond). 2018 Nov 29;132(22):2451-2467. doi: 10.1042/CS20180487. Print 2018 Nov 30.
There is increasing evidence that miRNAs, which are enriched in nanovesicles called exosomes, are important regulators of gene expression. When compared with normal pregnancies, pregnancies with gestational diabetes mellitus (GDM) are associated with skeletal muscle insulin resistance as well as increased levels of circulating placental exosomes. Here we investigated whether placental exosomes in GDM carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villous (CV) explants from both women with Normal Glucose Tolerant (NGT) and GDM pregnancies. Using miRNA sequencing, we identified a specific set of miRNAs selectively enriched with exosomes and compared with their cells of origin indicating a specific packaging of miRNAs into exosomes. Gene target and ontology analysis of miRNA differentially expressed in exosomes secreted in GDM compared with NGT are associated with pathways regulating cell migration and carbohydrate metabolism. We determined the expression of a selected set of miRNAs in placenta, plasma, and skeletal muscle biopsies from NGT and GDM. Interestingly, the expression of these miRNAs varied in a consistent pattern in the placenta, in circulating exosomes, and in skeletal muscle in GDM. Placental exosomes from GDM pregnancies decreased insulin-stimulated migration and glucose uptake in primary skeletal muscle cells obtained from patients with normal insulin sensitivity. Interestingly, placental exosomes from NGT increase migration and glucose uptake in response to insulin in skeletal muscle from diabetic subjects. These findings suggest that placental exosomes might have a role in the changes on insulin sensitivity in normal and GDM pregnancies.
越来越多的证据表明，富含称为外泌体的纳米囊泡的 miRNAs 是基因表达的重要调节剂。与正常妊娠相比，患有妊娠期糖尿病（GDM）的妊娠与骨骼肌胰岛素抵抗以及循环胎盘外泌体水平升高有关。在这里，我们研究了 GDM 胎盘外泌体是否携带与骨骼肌胰岛素敏感性相关的特定 miRNA 集。从正常葡萄糖耐量（NGT）和 GDM 妊娠妇女的绒毛膜绒毛（CV）外植体中分离出外泌体。通过 miRNA 测序，我们鉴定了一组特异性富集在外泌体中的 miRNA，并与它们的起源细胞进行了比较，表明 miRNA 特异性包装到外泌体中。与调节细胞迁移和碳水化合物代谢的途径相关的 GDM 与 NGT 相比，差异表达的 miRNA 的基因靶标和本体论分析与调节细胞迁移和碳水化合物代谢的途径相关。我们测定了 NGT 和 GDM 胎盘、血浆和骨骼肌活检中选定 miRNA 集的表达。有趣的是，这些 miRNA 在 GDM 胎盘、循环外泌体和骨骼肌中的表达呈一致模式变化。来自 GDM 妊娠的胎盘外泌体降低了来自正常胰岛素敏感性患者的原代骨骼肌细胞中胰岛素刺激的迁移和葡萄糖摄取。有趣的是，来自 NGT 的胎盘外泌体在糖尿病患者的骨骼肌中增加了对胰岛素的迁移和葡萄糖摄取。这些发现表明胎盘外泌体可能在正常和 GDM 妊娠中胰岛素敏感性变化中起作用。
