Extracellular cues and cellular conversations: The molecular choreography of embryo implantation

Infertility affects millions of people globally with recent statistics indicating that one in six adults is experiencing reproductive challenges at some point. For female infertility in particular, the global health burden is continuously intensifying with significant disparities across countries. Female infertility has a complex multifactorial etiology and understanding the underlying mechanisms is crucial in order to reduce the health burden and enhance patient well-being. For a pregnancy, successful embryo implantation is a pivotal step, requiring precise spatiotemporal synchronization between a competent blastocyst and a receptive endometrium during the window of implantation (WOI). This review provides an overview of recent developments around the molecular and clinical aspects of this process, with a specific focus on the extracellular microenvironmental cues and maternal-embryo interaction. Specifically, we detail the extensive extracellular matrix (ECM) remodeling that facilitates embryo adhesion and invasion, while shedding light on microRNAs as signaling and communication mediators that govern cell-cell and maternal-fetal interactions. Finally, we examine current limitations in the clinical assessment of receptivity and discuss future perspectives for non-invasive biomarkers and possibilities for more personalized solutions in assisted reproduction.