Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2

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.

Identification of key genes and crucial pathways for major depressive disorder using peripheral blood samples and chronic unpredictable mild stress rat models

“…For a better understand the roles of 10 hub genes, there is a need to perform a more systematic analysis through pathway enrichment in DAVID database. In particular, we found that the mTOR, which is involved in the regulation of autophagy and inflammation signaling pathway ( Chu et al, 2020 ; Yao et al, 2020 ) was enriched. Further study found that mTOR signaling pathway is inhibited in CUMS rat model, which is in agreement with the results reported previously ( Zhang et al, 2020 ; Zhuo et al, 2020 ).…”

“…SQSTM1 is involved in the regulation of autophagy and inflammation ( Chu et al, 2020 ; Yao et al, 2020 ). The serum level of TNFα was increased in MDD patients, which was associated with depressive symptoms ( Alvarez-Mon et al, 2021 ).…”

Human Umbilical Cord Mesenchymal Stem Cell (HUCMSC)-derived Exosomes as a Cell-Free Therapy for Soluble Fms-like Tyrosine Kinase-1 (Sflt-1)-induced Endothelial Dysfunction in Preeclampsia

“…Due in part to studying the paracrine effects of stem cell therapy, this speci c therapy has been mechanistically linked to the inherited functions of secreting exosomes [24]. Recently, research suggested HUCMSC-originated exosomes might be an innovative direction for therapeutic approaches against PE by accelerating trophoblast cell invasion and migration [21,25].…”

Identification and Analysis of Potential Autophagy-Related Biomarkers in Endometriosis by WGCNA

“…EZH2 silencing promoted autophagy in endometrial cancer cells. Meanwhile, by activating the mTOR signaling, its overexpression reduced the autophagy and survival of trophoblasts in the trophoblastic disease ( Wang et al, 2018 ; Chu et al, 2020 ). Furthermore, EZH2 has been identified to be a promising tumor biomarker ( Cai et al, 2011 ), and it represents a prognostic biomarker associated with immunosuppression in esophageal squamous carcinoma and hepatocellular carcinoma ( Liu et al, 2016 ; Guo et al, 2020 ).…”