Abstract
Human amnion-derived mesenchymal stem cells (AD-MSCs) have been reported as a promising effective treatment to repair tissue. Trophoblast dysfunction during pregnancy is significantly involved in the pathogenesis of preeclampsia (PE). To understand how AD-MSCs regulated trophoblast function, we treated trophoblasts with AD-MSC-derived exosomes under hypoxic conditions. The treatment markedly enhanced the trophoblast proliferation and autophagy. Furthermore, significant decrease of EZH2 levels and inactivation of mTOR signaling were observed in AD-MSC exosomes-treated trophoblasts. Consistent with these findings, overexpression of EZH2 activated the mTOR signaling in trophoblasts, and reduced the autophagy and survival of trophoblasts, even in the presence of AD-MSC-derived exosomes. In addition, EZH2 inhibition exhibited the same trophoblast autophagy-promoting effect as induced by AD-MSC-derived exosomes, also accompanied by the inactivation of mTOR signaling. Importantly, when EZH2 was overexpressed in trophoblasts treated with PQR620, a specific mTOR signaling inhibitor, the autophagy and proliferation in trophoblasts were decreased. Studies on human placental explants also confirmed our findings by showing that the expression levels of EZH2 and mTOR were decreased while the autophagy-associated protein level was increased by AD-MSC-derived exosome treatment. In summary, our results suggest that EZH2-dependent mTOR signaling inactivation mediated by AD-MSC-derived exosomes is a prerequisite for autophagy augmentation in hypoxic trophoblasts.
Highlights
Preeclampsia (PE) is a hypertensive disorder during pregnancy, and is associated with substantial maternal and perinatal complications (Hladunewich et al, 2007; Rana et al, 2019)
To further verify the autophagy-promoting effect of amnion-derived mesenchymal stem cells (AD-Mesenchymal stem cells (MSCs))-derived exosomes on trophoblasts, we examined the LC3-II/LC3-I ratio, BECN1 and P62 levels in trophoblasts treated with AD-MSC-derived exosomes by western blotting
According to the immunofluorescence assay results, AD-MSC-derived exosomes increased the staining intensity and area of punctate LC3-II in trophoblasts after 24 h of exposure to the hypoxic culture system (Figure 1D). These results indicated that the AD-MSCs promoted trophoblast proliferation and autophagy under hypoxic conditions by secreting exosomes
Summary
Preeclampsia (PE) is a hypertensive disorder during pregnancy, and is associated with substantial maternal and perinatal complications (Hladunewich et al, 2007; Rana et al, 2019). It is deemed to be one of the main causes of fetal and maternal death and morbidity across the world, and is reported to have a 2–8% incidence among pregnancies, in the developing countries (Tranquilli et al, 2012). Uteroplacental malperfusion caused by the trophoblast invasion failure and transformation of spiral arteries is considered as an important cause for this disorder (Ridder et al, 2019). Aberrant placental implantation can cause increased oxidative stress and hypoxia, which leads to inflammation and antiangiogenic protein release (Mol et al, 2016). Ischemia and hypoxia in trophoblasts are important pathological manifestations of PE
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