Uterus‐Mimetic Extracellular Microenvironment for Engineering Female Reproductive System

Abstract Addressing the complexities and challenges inherent in endometrial biology and regeneration, this study develops a uterus‐mimetic microenvironment to reconstitute the female reproductive system. Leveraging a decellularized uterus extracellular matrix (UEM), this approach supports the development and functions of endometrial organoids (EOs) more effectively than the current gold standard, Matrigel. Extensive proteomic analysis across eight different tissue‐derived matrices reveals that those closely mirroring the protein profile of UEM–especially those abundant in proteins specific to the female reproductive system–more effectively support EO growth. These proteins, particularly fibronectin, and decorin, are identified as key enhancers of EO development, with decorin notably amplifying Wnt7a gene expression, a pathway important for endometrial development. In vivo, UEM demonstrates remarkable efficacy in regenerative applications, notably enhancing epithelial regeneration and increasing pregnancy rates in an endometrium injury model. Moreover, the sophisticated in vitro modeling provided by UEM facilitates effective decidualization of endometrial stromal cells and structural superiority when co‐cultured with EOs, thus offering an enhanced platform for studying blastocyst implantation. Collectively, these findings demonstrate UEM's pivotal role in reconstituting the reproductive system, highlighting its effectiveness in producing organoids that are not only structurally and functionally robust but also therapeutically potent.