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Review
. 2023 Aug 31;137(16):1311-1332.
doi: 10.1042/CS20220150.

Extracellular vesicle-mediated targeting strategies for long-term health benefits in gestational diabetes

Soumyalekshmi Nair  1 , Valeska Ormazabal  2 , Flavio Carrion  3 , Aase Handberg  4 , H David McIntyre  5 , Carlos Salomon  1   3
Affiliations
Review

Extracellular vesicle-mediated targeting strategies for long-term health benefits in gestational diabetes

Soumyalekshmi Nair et al. Clin Sci (Lond). .

Abstract

Extracellular vesicles (EVs) are critical mediators of cell communication, playing important roles in regulating molecular cross-talk between different metabolic tissues and influencing insulin sensitivity in both healthy and gestational diabetes mellitus (GDM) pregnancies. The ability of EVs to transfer molecular cargo between cells imbues them with potential as therapeutic agents. During pregnancy, the placenta assumes a vital role in metabolic regulation, with multiple mechanisms of placenta-mediated EV cross-talk serving as central components in GDM pathophysiology. This review focuses on the role of the placenta in the pathophysiology of GDM and explores the possibilities and prospects of targeting the placenta to address insulin resistance and placental dysfunction in GDM. Additionally, we propose the use of EVs as a novel method for targeted therapeutics in treating the dysfunctional placenta. The primary aim of this review is to comprehend the current status of EV targeting approaches and assess the potential application of these strategies in placental therapeutics, thereby delivering molecular cargo and improving maternal and fetal outcomes in GDM. We propose that EVs have the potential to revolutionize GDM management, offering hope for enhanced maternal-fetal health outcomes and more effective treatments.

Keywords: Extracellular Vesicles; Pregnancy; insulin resistance; microRNA; skeletal muscle.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Placenta is central to metabolic regulation in pregnancy and mediates the short and long term consequences of GDM
Several risk factors contribute to the development of GDM. Hormones and proinflammatory cytokines released from placenta regulate the insulin response in glucose homeostasis organs such as skeletal muscle, adipose tissue and liver, and insulin secreting pancreas and reprogram the maternal metabolism in healthy pregnancy and GDM. The metabolic derangement in GDM causes maternal hyperglycemia and the excess glucose and metabolites are transferred to fetus leading to short- and long-term consequences.
Figure 2
Figure 2. Placental EVs regulate insulin response and glucose homeostasis in target cells
Placenta secretes a wide range of EVs into the maternal circulation. Placental EVs in GDM have differential expression of proteins and miRNAs compared with NGT EVs. GDM EVs induce glucose intolerance by decreasing the insulin sensitivity, phosphorylated IRS-1 and phosphorylated Akt expression in skeletal muscle. Placental EVs in GDM alter the DPP-4 activity in pancreas and increase the proinflammatory response and oxidative stress in different tissues. These changes lead to dysregulated glucose metabolism in cells and contribute to the metabolic derangement in GDM
Figure 3
Figure 3. Engineering parent cells and EVs for targeted interventions in GDM
EV-releasing cells could be engineered to produce EVs with surface expression of specific molecules that target placenta and could be loaded with therapeutic molecule. Also, natural EVs released from cells could be modified to express surface targeting molecule and therapeutic cargo incorporated using different methods to produce therapeutic EVs. These engineered EVs could be used for targeting placenta leading to changes in placental function and gene expression and leading to potential health benefits to women with GDM and their offspring.
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