Integrative Omics Analysis Revealed That the Metabolic Changes in Placental Cells from Gestational Diabetes Mellitus Are Reflected in Their Secreted Exosomes

Exosomes are membrane-bound extracellular vesicles secreted from a range of cells including human placental cells and contain specific cargo such as proteins, and miRNAs. The aim of this study was to determine the miRNA and protein profile in primary human trophoblast (PTH) and their secreted exosomes obtained from placentae from women with normal glucose tolerant (NGT) and gestational diabetes mellitus (GDM). Using quantitative proteomic analysis, 34 proteins were significantly different in PTH from GDM compared with NGT. Similarly, a specific set of proteins were significantly different in PTH exosomes from GDM compared with NGT. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from PTH and exosomes. We identified a set of miRNAs (miR-181, miR-151, miR-10a, miR-744, miR-1468 and miR-4507) which their expression varied in a consistent pattern in PTH and their secreted exosomes in GDM compared with NGT. Interestingly, a specific set of proteins and miRNAs were selectively enriched with exosomes and compared with their PTH of origin in NGT and GDM indicating a specific packaging of proteins and miRNAs into exosomes. We used Ingenuity Pathway Analysis (IPA) analysis to identify miRNA-gene interactions using the miRNA and proteomic data and created a network link with the down- and up-regulated pairs of miRNA-proteins. IPA core analysis showed that the top canonical pathway associated with these miRNAs were PI3/AKT signalling and glucose metabolism/insulin resistance, respectively. We proposed that exosomes are “fingerprints” of the releasing cells and their metabolic status. Exosomes released from placenta can modify the phenotype of target cells, inducing metabolic changes in GDM to contribute to changes in insulin sensitivity during pregnancy. Disclosure S. Nair: None. N. Jayabalan: None. D. Guanzon: None. A. Lai: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. M. Lappas: None. C. Salomon: None. Funding Diabetes Australia; Fondo Nacional de Desarrollo Cientifico y Tecnologico (1170809)