The promise of placental extracellular vesicles: models and challenges for diagnosing placental dysfunction in utero†

Abstract

Monitoring the health of a pregnancy is of utmost importance to both the fetus and the mother. The diagnosis of pregnancy complications typically occurs after the manifestation of symptoms, and limited preventative measures or effective treatments are available. Traditionally, pregnancy health is evaluated by analyzing maternal serum hormone levels, genetic testing, ultrasonographic imaging, and monitoring maternal symptoms. However, researchers have reported a difference in extracellular vesicle (EV) quantity and cargo between healthy and at-risk pregnancies. Thus, placental EVs (PEVs) may help to understand normal and aberrant placental development, monitor pregnancy health in terms of developing placental pathologies, and assess the impact of environmental influences, such as infection, on pregnancy. The diagnostic potential of PEVs could allow for earlier detection of pregnancy complications via noninvasive sampling and frequent monitoring. Understanding how PEVs serve as a means of communication with maternal cells and recognizing their potential utility as a readout of placental health have sparked a growing interest in basic and translational research. However, to date, PEV research with animal models lags behind human studies. The strength of animal pregnancy models is that they can be used to assess placental pathologies in conjunction with isolation of PEVs from fluid samples at different time points throughout gestation. Assessing PEV cargo in animals within normal and complicated pregnancies will accelerate the translation of PEV analysis into the clinic for potential use in prognostics. We propose that appropriate animal models of human pregnancy complications must be established in the PEV field.

Keywords: adverse pregnancy outcomes; animal models; exosome; extracellular vesicle; placenta.

Figure 1

Schematic diagram of human placental villous structure and PEV biogenesis. Placental structure with increasing magnification (organ level, tissue level, cellular level) is depicted at the left, along with apoptotic body, microvesicle, and exosome biogenesis in a trophoblast cell. A key for molecular elements is at the upper left. Top right: Apoptotic bodies form when a cell is undergoing apoptosis, as depicted by the breakdown of the nucleus and packaging of DNA and organelles. Middle right: Microvesicles are formed via pinching off of the plasma membrane, entrapping molecular cargo. Bottom right: Exosomes are assembled within the secretory pathway. Secretory vesicles (SV) are released by the golgi body and can fuse with endosomes (END). Endosomes can also fuse together or fuse with the lysosome (LYS) for cargo degradation. Late stage endosomes are also referred to as MVBs if they contain intraluminal vesicles (depicted as small light yellow vesicles inside the MVB). All of these vesicles are then released into the maternal bloodstream. Some cargo and membrane proteins specific to the different EV classes are depicted. Lipid composition is depicted in a simplified, grouped manner on the border of the vesicles (green, phosphatidylserine; blue, phosphatidylcholine; purple, phosphatidylethanolamine), with the percent of each lipid content indicated adjacent to the membrane region. The gray membrane of the vesicles represents other lipids that have been identified including sphingomyelin, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, bis-monoacylglycerophosphate, cardiolipin, lysophosphatidylcholine, and lysophosphatidylethanolamine [35].

Figure 2

Experimental models of human pregnancy. Laboratory animal models (NHP, guinea pig, rodent, and rabbit), large animal models (pig, sheep, and cow), and in vitro systems (placental perfusion, tissue/cell culture, and blood) are depicted to represent the experimental models of human pregnancy.