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.

Bioengineering approaches for the endometrial research and application

“…Estradiol-loaded HAECM scaffolds upregulate a series of growth factors, including epidermal growth factor, insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor, which are conducive to the growth of endometrial cells [ 108 ]. Decellularized scaffolds based on the human endometrium or uterus are beneficial for personalized regenerative medicine in patients with infertility because they specifically inherit diverse pathological characteristics from different patients [ 109 ]. Moreover, the therapeutic potential of the uterus-derived decellularized scaffolds is also attributed to altering the frequency of natural killer (NK) cells located in the endometrium, a crucial immune cell group responsible for a favorable environment for endometrial decidualization [ 109 ].…”

“…Decellularized scaffolds based on the human endometrium or uterus are beneficial for personalized regenerative medicine in patients with infertility because they specifically inherit diverse pathological characteristics from different patients [ 109 ]. Moreover, the therapeutic potential of the uterus-derived decellularized scaffolds is also attributed to altering the frequency of natural killer (NK) cells located in the endometrium, a crucial immune cell group responsible for a favorable environment for endometrial decidualization [ 109 ]. Besides, these typical scaffolds are reported to protect the body from the potential immunogenicity of the materials, making them practical and safer alternatives for clinical applications [ 101 ].…”

Injectable “Homing‐Like” Bioactive Short‐Fibers for Endometrial Repair and Efficient Live Births

“…[ 32 ] Currently, ECM‐related approaches for endometrial restoration include the utilization of stem cell‐ and growth factor‐loaded ECM hydrogels, as well as ECM scaffolds extracted from various sources such as the endometrium, uterus, amnion, and bladder. [ 33–39 ] Despite considerable progress achieved in the use of decellularized ECM for endometrial repair, several limitations still exist: 1) ECM materials need to be equipped with exogenous stem cells, which cannot mobilize in situ uterine cells for repair, and the clinical use of stem cells may have risks such as tumor formation. 2) It is difficult for existing ECM materials to retain active growth factors due to preparation methods and other reasons, so it is necessary to carry exogenous cytokines for tissue repair.…”