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Abstract

A direct interaction between the extraembryonic and the uterine tissues during embryo implantation generates a unique biomechanical context for the blastocyst. However, our mechanistic understanding of the regulation of blastocyst morphogenesis during implantation is limited by the inaccessibility in vivo and remaining challenges to model feto-maternal interaction ex vivo. To overcome these limitations, I applied microfabrication and biomaterial engineering to model biomechanical cues of the murine intrauterine environment ex vivo with high precision and tunability. I identify that embryo-uterine adhesion and tissue geometry are critical for successful peri-implantation development. In a specific parameter range, closely resembling in utero conditions, the 3D geometrically patterned hydrogel supports mouse blastocysts through implantation and enables robust peri-implantation morphogenesis; promotes the development of the Reichert’s membrane and all extraembryonic tissues, including giant trophoblast, which directly interacts with the uterus.

To monitor in toto peri-implantation embryo dynamics, the culture method was integrated with inverted view InVi-SPIM and multiview MuVi-SPIM light-sheet microscopes. I show that integrin-mediated adhesion by the mural trophectoderm provides the mechanism of trophectoderm tension release, driving the morphogenesis of the extraembryonic ectoderm and egg cylinder patterning. Moreover, the embryo-uterine adhesion enables collective trophoblast migration, dependent on Rac1. Finally, I demonstrate that the uterine tissue geometry spatially coordinates collective trophoblast migration to delineate space for egg cylinder growth. Together, this study reveals essential mechanisms of dynamic embryo-uterus interactions during peri-implantation development.