As shown in our previous studies, growth and metastasis of ovarian cancer can be regulated by adipose-derived mesenchymal stem cells (ADSCs). However, the underlying mechanism has not yet been revealed. In this study, a proteomics analysis was performed to compare protein expression treated with and without ADSCs in ovarian cancer cells. Protein levels were altered in ovarian cancer cells due to the treatment of ADSCs. Thymosin beta 4 X-linked (TMSB4X) levels changed dramatically, and this protein was identified as one of the most important candidate molecules contributing to the tumour-promoting effects of ADSCs. Compared with the cells that are cultured in the normal growth medium, the TMSB4X levels cultured in ADSC-conditioned medium increased significantly in ovarian cancer cells. Furthermore, the growth and invasion of cancer cells were decreased, even in the ADSC-conditioned medium treatment group (P < 0.05), by the inhibition of TMSB4X. As shown in the bioluminescence images captured in vivo, increased ovarian cancer's growth and metastasis, along with elevated TMSB4X expression, were observed in the group of ADSC-conditioned medium, and the tumour-promoting effect of ADSCs was attenuated by the inhibition of TMSB4X. Based on our findings, increased TMSB4X expression may play a role in accelerating the ADSC-mediated proliferation, invasion, and migration of ovarian cancers.

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.

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Background Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. Results To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. Conclusion In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts. Graphic abstract

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