Placenta-derived exosomes: potential biomarkers of preeclampsia

Figures & data

Figure 1 Classification of hypertensive disorders in pregnancy.

Notes: Hypertensive disorders with preeclampsia subclassified into early- and late-onset preeclampsia. Adverse conditions are defined as conditions that increase the risk of severe complications. Adverse conditions and severe complications are categorized into the organ system affected (ie, central nervous system, cardiorespiratory, hematological, renal, hepatic, and fetoplacental), as described by Magee et al.^{25 a}Hypertension present either at prepregnancy or that developed at 20 weeks prior to gestation.

Table 1 Overview of potential, combined and candidate biomarkers in preeclampsia

Biomarker	Biomarker type	Detection stage	Role	Sensitivity	Specificity	Advantages	Disadvantages	Reference(s)
Potential biomarkers/combined biomarkers
Cystatin C	Protein	Preclinical (first trimester: ≥11 weeks)	Protease inhibitor involved in impaired renal function and hypothesized to disrupt placental development in PE	91.7	85.7	May be a useful first-trimester biomarker due to its elevation in overt PE, with a 93% detection rate when used in combination with maternal BMI	Indirect measure of glomerular filtration impairment and may be unrelated to placental dysfunction; may have application in severe preeclampsia, though the possibility that this occurs as a result of renal impairment due to increase protein load in maternal circulation should not be excluded The study was inconclusive, as data regarding clinical markers, such as arterial pressure and Doppler PI were not been measured; inclusion of other HDPs need to be taken into consideration in future studies	^Citation114
HTRA3	Enzyme	Clinical (second trimester: 13–14 weeks)	Serine protease found to be associated with alterations in placental oxygen transfer, and thus may be involved in blood-vessel remodeling	ND	ND	Elevation of HTRA3 in PE indicates biomarker potential; additionally, the ratio of HTRA3-L to total HTRA3 was lower in early-onset PE	Involvement of the enzyme in the pathogenesis of PE is unknown; enzyme not a marker of placental function and thus cannot be used as a specific marker of placental function in PE	^Citation62
NGAL	Glycoprotein	Clinical (late second trimester, early third trimester: 24–26 weeks)	Involved in the modulation of oxidative stress in normal cellular physiology; its dysregulation has been associated with inflammation and cancer	75	94.5	Elevated levels of NGAL obtained in PE that were positively correlated with blood pressure and proteinuria	Involvement of NGAL in pathophysiology of PE unknown; findings need to evaluated in larger population	^Citation66
PP13	Protein	Preclinical (first trimester: 6–10 weeks)	Immunoregulatory protein involved in placental development	80	20	Significantly reduced levels of PP13 found in PE in early pregnancy and thus may have application as potential early predictor of PE	Marker has poor detection sensitivities, and detection has to be based on predetermined cutoff values	^Citation72
Serum lipids	Oxidized cholesterol and glycerophosphocholine	Preclinical (first trimester: 6–10 weeks)	Lipids like oxidized cholesterol contribute to vascular atherosclerosis	91	82	Combined lipid biomarkers show good ability to detect PE in early pregnancy	Role of these lipids still unknown in pathogenesis of PE; in addition, further studies required to determine if these markers are specific for PE or associated with all types of pregnancy-related complications	^Citation76
IL10, TNFα, and IFNγ	Cytokines	Clinical (second trimester: 14–18 weeks)	IL10 is an important anti- inflammatory cytokine in pregnancy that inhibits upregulation of MMP2 and MMP9 and promotes the termination of Th1 inflammatory rejection reactions against the fetal placental unit TNFα involved in systemic endothelial cell activation IFNγ associated with idiopathic recurrent spontaneous abortion	ND	ND	Reduced levels of these cytokines may be involved in the modulation of etiopathogenesis of PE and thus show promise as early clinical stage biomarker	Larger population size required to validate biomarker potential	^Citation55, ^Citation56
RASSF1A	cfDNA/cffDNA	Clinical (second trimester: 17–30 weeks)	It is hypothesized that the reason cffDNA increases in maternal circulation before onset of the clinical symptoms is increased placental perfusion caused by inadequate spiral-artery remodeling; oxidative stress, apoptosis, and necrosis the main physiological processes that disrupt placental development, leading to increase levels of cfDNA and cffDNA in maternal circulation	87.5/100	75/50	Reliable predictor of PE with ROC (AUC) values of 0.94 and 0.83 for cfDNA and cffDNA, respectively; predictive capability of woman with risk of PE who developed PE and woman at risk who did not develop PE had an ROC (AUC) value of 0.78 and 0.81 for cfDNA and cffDNA, respectively; combined cfDNA and cffDNA quantification of RASSF1A may be used as a late preclinical stage biomarker in women with high risk of PE	Cannot be used as a very early biomarker (0–16 weeks of gestation) cffDNA has low specificity and thus needs to be used in combination with cfDNA The exact physiological role of these molecules in PE has not been elucidated	^Citation50, ^Citation51
Combined clinical markers/potential biomarkers
MFs, MAP, UtA PI, PGF, PAPPA	Clinical measurements, angiogenic factor, and protein	Preclinical (first trimester: 11–13 weeks)	Clinical markers (MFs, MAP, and UtA PI) direct measures of cardiac malfunction PGF an angiogenic factor required for normal placental development PAPPA involved in cellular proliferation	ND	ND	Combined markers have potential to detect severe EOPE at detection rate of 93% with false- positive rate of 5% Algorithm for the detection of severe EOPE may serve as a useful screening tool Method has a greater detection rate of PE than previous traditional methods, which relied entirely on maternal history	Poor detection rates for LOPE (35%) and GH (18.3%) obtained; this proves that the combined marker cannot differentiate between PE subtypes	^Citation31
MFs, MAP, UtA PI, PAPPA, free βhCG	Clinical measurements, protein, and hormone	Preclinical (first trimester: 8–12 weeks)	βhCG involved in implantation and blastocyst development and replaced PGF in Poon et al^Citation31	ND	ND	At a false-positive rate of 5%, 10% detection rates for EOPE were 69.2% and 80.8%; however, LOPE-detection rates were lower at 29.4% and 39.6% May be a useful tool in early screening of EOPE	Cannot differentiate between PE subtypes Cannot be used as screening test, as larger studies with inclusion of angiogenic factors are required to validate potential to be used in differential diagnosis of PE	^Citation29
Combined candidate biomarkers
sFlt1 and PGF	Angiogenic and antiangiogenic factors	Clinical (third trimester: 20–33 weeks)	Directly involved in the pathogenesis of PE; PGF and angiogenic factor required for normal placental development and sFlt1 an antiangiogenic factor	88–95	94–99.5	Ability to detect PE with high sensitivity and specificity. In addition, differential phase cutoffs improve the diagnostic accuracy of the ratio Favorable sensitivity and specificity are attributed to their direct involvement in normal pregnancy	Larger studies required to validate differential diagnosis, due to high constructed incidence of PE in this study and multifactorial nature of the disorder Cannot be used as an early biomarker of PE	^Citation38

Abbreviations: BMI, body-mass index; EOPE, early-onset PE; GH, gestational hypertension; HDPs, hypertensive disorders of pregnancy; LOPE, late-onset PE; MAP, mean arterial pressure; MFs, maternal factors; ND, not determined; PE, preeclampsia; UtA PI, uterine-artery pulsatility index; βhCG, β-human chorionic gonadotropin.

Figure 2 Potential biomarkers involved in the pathogenesis of preeclampsia (PE).

Notes: (A) Proangiogenic and (B) anti-angiogenic factors associated with improper spiral-artery remodeling in PE. (C) Immune factors associated with the pathogenesis of PE as a result of the predominant T_h1 immunity of the disorder. ⁺Significantly increased expression in comparison to normal pregnancy; ⁻significantly lowered expression in comparison to PE pregnancies.

Abbreviations: MSIR, maternal systemic inflammatory response; T_h, T-helper.

Figure 3 Hypothetical model of exosomes in relation to immunological and clinical outcomes in EOPE, LOPE, and normal pregnancy.

Notes: (A) In EOPE, an increase in placenta-derived and total exosomes in comparison to normal pregnancy mediates a shift toward T_h1 immunity and thus results in an exaggerated MSIR. (B) In normal pregnancy, there is a balance between placenta-derived and total exosomes that mediates a shift toward T_h2 immunity, thereby maintaining a balanced MSIR, a requirement for successful pregnancy. (C) In LOPE, the increase in total and decrease in placenta-derived exosomes in comparison to normal pregnancy mediates a shift toward T_h1 immunity, which exaggerates the MSIR to a degree that does not exceed the MSIR in EOPE. (A, C) Alteration in the magnitude of placenta-derived and total-exosomes during the manifestation of LOPE or EOPE results in adverse conditions or severe complications that lead to the clinical manifestation of severe PE or eclampsia.

Abbreviations: EOPE, early-onset preeclampsia; LOPE, late-onset PE; MSIR, maternal systemic inflammatory response; T_h, T-helper.

Figure 4 Schematic representation of key pregnancy-associated exosomal molecular cargo and their function.

Notes: This figure highlights key transmembrane and cytosolic proteins involved in immunomodulation during normal pregnancy. Key pregnancy-associated exosomal nucleic acids have not been identified to date. Common exosomal markers are not shown.

Abbreviation: PBMCs, peripheral blood mononuclear cells.

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