Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window
Emma S. Lucas, Pavle Vrljicak, Joanne Muter, Maria Diniz-da-Costa, Paul J. Brighton, Chow‐Seng Kong, Julia Lipecki, Katherine Fishwick, Joshua Odendaal, Lauren Ewington, Siobhan Quenby, Sascha Ott, Jan J. Brosens
Abstract
During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.