Chorionic villus-derived mesenchymal stem cell-mediated NRG1 upregulation promotes HTR-8/SVneo cells proliferation through the activation of the NF-κB signaling pathway

In a prior study, our group found that chorionic villus-derived mesenchymal stem cells (CV-MSCs) were capable of promoting trophoblast proliferative and invasive activity. The mechanistic basis for this activity, however, has yet to be clarified. As such, an RNA-Seq analysis was conducted using trophoblasts that were treated with or without CV-MSC-conditioned media. Of the differentially expressed genes identified when comparing these two groups of cells, 23 proliferation-associated genes were identified and knocked down to test their functional roles in trophoblasts. These analyses revealed that inhibiting neuregulin 1 (NRG1) expression was sufficient to suppress proliferation and induce cell cycle arrest in trophoblasts. Placental samples from patients with preeclampsia exhibited significantly increased NRG1 expression relative to samples from healthy pregnancies. Following treatment with CV-MSC-conditioned media, NRG1 was upregulated in trophoblasts at the mRNA and protein levels. Relative to control trophoblasts, those in which NRG1 had been knocked down exhibited significantly impaired proliferation and DNA replication with the inactivation of the NF-κB signaling pathway. In contrast, overexpressing NRG1 yielded the opposite trophoblast phenotypes. Even in cells overexpressing NRG1, inhibition of NF-κB signaling was sufficient to significantly suppress trophoblast proliferation (P < 0.05). These results indicate that elevated NRG1 expression may play a role in the ability of CV-MSCs to induce proliferative activity in trophoblasts through the NF-κB signaling axis.