Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction

Abstract

Placental dysfunction refers to the insufficiency of placental perfusion and chronic hypoxia during early pregnancy, which impairs placental function and causes inadequate supply of oxygen and nutrients to the fetus, affecting fetal development and health. Fetal intrauterine growth restriction, one of the most common outcomes of pregnancy-induced hypertensions, can be caused by placental dysfunction, resulting from deficient trophoblast syncytialization, inadequate trophoblast invasion and impaired vascular remodeling. During placental development, cytotrophoblasts fuse to form a multinucleated syncytia barrier, which supplies oxygen and nutrients to meet the metabolic demands for fetal growth. A reduction in the cell fusion index and the number of nuclei in the syncytiotrophoblast are found in the placentas of pregnancies complicated by IUGR, suggesting that the occurrence of IUGR may be related to inadequate trophoblast syncytialization. During the multiple processes of trophoblasts syncytialization, specific proteins and several signaling pathways are involved in coordinating these events and regulating placental function. In addition, epigenetic modifications, cell metabolism, senescence, and autophagy are also involved. Study findings have indicated several abnormally expressed syncytialization-related proteins and signaling pathways in the placentas of pregnancies complicated by IUGR, suggesting that these elements may play a crucial role in the occurrence of IUGR. In this review, we discuss the regulators of trophoblast syncytialization and their abnormal expression in the placentas of pregnancies complicated by IUGR.

Oncostatin M and STAT3 Signaling Pathways Support Human Trophoblast Differentiation by Inhibiting Inflammatory Stress in Response to IFNγ and GM-CSF

“…Indeed, as described during the in vitro VST differentiation of human chorionic villi trophoblasts and BeWo cells, E-cadherin levels are significantly increased during earlier stages of syncytialization but rapidly decreased as syncytialization progresses in the spontaneous and induced syncytialization systems [72]. Although the literature regarding the relationship between E-cadherin expression and gestational pathologies is controversial, it is predominantly in the direction of an increased expression of E-cadherin in PE and FGR [73,74]. In this context, we found that IFNγ and GM-CSF also had opposing effects on morphologic trophoblast differentiation, with IFNγ increasing E-cadherin expression, whereas GM-CSF reduced it in VST/BW cells.…”

Exploring the causal effect of placental physiology in susceptibility to mental and addictive disorders: a Mendelian randomization study

“…The reduced blood flow to the fetus will cause a lower or intermittent provision of nutrients and oxygen, and there could be episodes of oxidative stress that can lead to a misfolded protein accumulation (51,52). Hypoxic conditions have also been linked to a reduced activity of differentiation pathways of trophoblasts, such as syncytialization (53,54). Thus, a maternal-fetal interface imbalance mediated by impaired trophoblast function may compromise the normal development of the large human fetal brain, taking into account its high demand of oxygen and nutrients (15,55).…”

Prediction of Early- and Late-Onset Pre-Eclampsia in the Preclinical Stage via Placenta-Specific Extracellular miRNA Profiling

“…It is known that hypoxia plays a different role in placentogenesis depending on gestational age: in the first trimester of pregnancy, it promotes trophoblast invasion and angiogenesis [58], but a prolonged hypoxic condition beyond the first trimester causes deficient trophoblast syncytialization, inadequate trophoblast invasion, and impaired vascular remodeling, resulting in placental dysfunction and pregnancy-induced hypertension such as pre-eclampsia/intrauterine growth restriction [59,60]. Some miRNAs are hypoxia-responsive molecules [61][62][63], and among which are placenta-specific miR-NAs, identified in the present study as being pre-eclampsia-associated markers.…”