Embryo implantation factors from the uterus are associated with ectopic implantations

Abstract

Implantation is crucial to establishing a viable pregnancy, and abnormal implantation can render ectopic pregnancies, recurrent losses, and placenta accrete spectrum (PAS). To better understand the pathophysiology of disrupted implantation, we studied how free-floating oviductal and uterine cells lead to ectopic lesions, or endosalpingiosis (ES) and endometriosis, respectively. We developed a novel mouse model to interrogate the role of implantation signaling factors in ES. We developed a mouse model of ES using auto-fluorescing oviductal tissue, using female mice as the donors and male mice as the recipients in order to eliminate uterine factors related to extra-uterine implantation (Figure 1). Donors were treated with degarelix (Deg) to arrest the estrus cycle or were synced to a normal estrus cycle [vehicle control (VC)]. Donor oviductal (OD) and endometrial (EM) tissues were harvested. Recipients received donor tissue alone or tissue co-injected with leukemia inhibitory factor (LIF) to reintroduce an implantation factor. At one month, the recipients were euthanized to count auto-fluorescing lesions. Transfer of donor VC + LIF OD tissue resulted in significantly more lesions in recipients (6.33 lesions/mouse (L/M), p< 0.01) compared to the transfer of donor Deg and Deg + LIF OD tissue (2.00 and 3.25 L/M respectively, Figure 2). Transfer of donor Deg and Deg + LIF EM tissue resulted in significantly fewer lesions in the recipients (2.25 and 2.33 L/M, p< 0.001) compared to the transfer of donor VC and VC + LIF EM tissue (6.67 and 8.00 L/M). Implantation factors initiate and promote ectopic tissue growth, notably in the absence of any uterine factors. Our novel model demonstrates that removing EM implantation factors with Deg reduced ectopic growth. Adding back implantation factors like LIF increased OD tissue implantation. Identifying the role of these implantation factors in promoting or preventing abnormal implantation will help us better understand drivers of early pregnancy successes, failures, and complications.View Large Image Figure ViewerDownload Hi-res image Download (PPT)