Chorionic villus-derived mesenchymal stem cell-mediated autophagy promotes the proliferation and invasiveness of trophoblasts under hypoxia by activating the JAK2/STAT3 signalling pathway

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. 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. In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts.