Uterus‐Derived Decellularized Extracellular Matrix‐Mediated Endometrial Regeneration and Fertility Enhancement

Abstract Tissue‐specific decellularized extracellular matrix recapitulates the complexity of natural ECMs, creating an organ‐specific microenvironment based on its intrinsic characteristics. Here, hydrogels containing uterus‐derived decellularized extracellular matrix (UdECMs) from the endometrium‐specific layer or the entire uterus are developed. UdECMs serve as effective organ‐specific biomaterials, displaying that intrauterine UdECM administration induces endometrial regeneration and fertility enhancement. Moreover, UdECM administration alters the profile of natural killer cell subpopulations to exhibit more mature and less cytotoxic features, providing a favorable uterine environment for successful implantation and decidualization. Interestingly, insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 as key regulatory factors that contribute to UdECM‐mediated endometrial regeneration are discovered. Furthermore, ex vivo culture of human uterine tissues reveals that UdECMs of different origins exhibit distinct therapeutic effects based on the endometrial conditions of patients, suggesting their uses as a therapeutic intervention providing personalized regenerative medicine for infertile patients with a poor uterine environment.