Abstract
Embryo implantation requires the breaching of the endometrial luminal epithelium (LE) to facilitate invasion. In this study, we report that during implantation, endometrial LE cells undergo partial epithelial-to-mesenchymal transition (pEMT) specifically at the implantation sites. This pEMT in the LE is critical, as the in vivo knockdown of the EMT transcription factor Twist2 inhibits embryo implantation. Furthermore, we observed a reduction in the expression of the transcription factor HOXA10 in LE cells at the implantation sites. Interestingly, LE cells of HOXA10-hypomorphic mice and human endometrial epithelial cells (RL95-2) with HOXA10 knockdown (HOXA10KD) also undergo pEMT and acquire a migratory phenotype in vitro, suggesting that the loss of HOXA10 drives pEMT in the endometrial epithelium. The HOXA10KD cells have a higher pEMT score and differential expression of genes associated with cell migration and TGF-β signaling pathways. We also determined the genome-wide occupancy sites of HOXA10 in human endometrial epithelial cells and identified 1,246 direct targets that had significant roles in EMT. Collectively, our findings suggest that HOXA10 is required to maintain an epithelial state and its loss activates mesenchymal genes resulting in a pEMT phenotype. This adds HOXA10 as a member of the MET inducer team that engage in mutually inhibitory feedback loops directly or indirectly with EMT inducer team. In summary, our study establishes that pEMT in the LE as a critical step for embryo implantation and reveals that HOXA10 regulates this process.
Competing Interest Statement
The authors have declared no competing interest.
