Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus

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Abstract

Background

Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile.

Methods

Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status ( i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM.

Results

A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake.

Conclusions

During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-021-02999-9.

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Most cited references 66

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STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

Damian Szklarczyk, Annika L Gable, David Lyon … (2018)

Abstract Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein–protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein–protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.

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Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Clotilde Théry, Kenneth W Witwer, Elena Aikawa … (2019)

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

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Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

Hadi Valadi, Karin Ekström, Apostolos Bossios … (2007)

Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).

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Author and article information

Contributors

Carlos Salomon:

ORCID: http://orcid.org/0000-0003-4474-0046

c.salomongallo@uq.edu.au , https://clinical-research.centre.uq.edu.au/

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 20 August 2021

Publication date PMC-release: 20 August 2021

Publication date Collection: 2021

Volume: 19

Electronic Location Identifier: 360

Affiliations

[1 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, , The University of Queensland, ; Building 71/918, Herston, QLD 4029 Australia

[2 ]GRID grid.5380.e, ISNI 0000 0001 2298 9663, Faculty of Biological Sciences, Pharmacology Department, , University of Concepcion, ; Concepción, Chile

[3 ]GRID grid.5380.e, ISNI 0000 0001 2298 9663, Faculty of Medicine, Department of Obstetrics and Gynaecology, , University of Concepcion, ; Concepción, Chile

[4 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Obstetrics and Gynaecology, , University of Melbourne, ; Melbourne, Australia

[5 ]GRID grid.415379.d, ISNI 0000 0004 0577 6561, Mercy Hospital for Women, ; 163 Studley Road, Heidelberg, VIC 3084 Australia

[6 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Fetal Medicine Research Center, , BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), ; Barcelona, Spain

[7 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Mater Research, Faculty of Medicine, , University of Queensland, ; Mater Health, South Brisbane, Australia

Author information

Carlos Salomon http://orcid.org/0000-0003-4474-0046

Article

Publisher ID: 2999

DOI: 10.1186/s12967-021-02999-9

PMC ID: 8377872

PubMed ID: 34416903

SO-VID: 6d8288bb-14c9-4d8f-88f9-a983e6dc5819

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 February 2021

Date accepted : 23 July 2021

Funding

Funded by: Lions Medical Research Foundation

Funded by: Diabetes Australia

Funded by: National Health and Medical Research Council

Award ID: 1195451

Award Recipient : Carlos Salomon

Funded by: FundRef http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;

Award ID: 1170809

Award Recipient : Carlos Salomon

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: pregnancy,exosomes,mirnas,insulin resistance,skeletal muscle

Data availability:

ScienceOpen disciplines: Medicine

Keywords: pregnancy, exosomes, mirnas, insulin resistance, skeletal muscle

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Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus

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Karger: Nutrition and Dietetics

Most cited references 66

STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

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Cited by 18

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