Chorionic Villus-Derived Mesenchymal Stem Cell-Mediated Autophagy Promotes Proliferation and Invasiveness of Trophoblasts Under Hypoxia by Activating the JAK2/STAT3 Signalling Pathway

Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) operate in regulation of trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. The treatment markedly enhanced proliferation and invasion ability and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. We further found that STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, inhibition of JAK2/STAT3 signalling reduced 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, overexpression of STAT3 increased the levels of autophagy in trophoblasts; thus, it regulated positively autophagy in hypoxic trophoblasts. Human placental explants also proved our finding, in which STAT3 was activated and LC3B-II levels were increased by CV-MSC treatment. In summary, our data suggest that CV-MSC-dependent activation of JAK2/STAT3 signalling is a prerequisite for upregulation of autophagy in trophoblasts. Funding Statement: This study was supported by the Clinical Medicine+X Project of the Affiliated Hospital of Qingdao University. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Placentas (n = 2) were obtained from full‑ term births after caesarean section with parental permission. In line with the ethical protocols of the Affiliated Hospital of Qingdao University, China, every procedure was conducted accordingly.