Self‐Assembled Peptide Hydrogels Loaded with Umbilical Cord‐Derived Mesenchymal Stem Cells Repairing Injured Endometrium and Restoring Fertility

Abstract Endometrial injury is a major cause of infertility and recurrent miscarriage. However, no clinically available methods currently exist to effectively repair the damaged endometrium. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for promoting tissue regeneration, yet a biocompatible scaffold capable of delivering MSCs and supporting their growth is needed. Herein, the study reports a peptide hydrogel scaffold, self‐assembled from a peptide IVK8‐RGD consisting of an ionic complementary peptide sequence IEVEIRVK and a bioactive sequence RGD, to load umbilical cord‐derived mesenchymal stem cells (UC‐MSCs). This peptide forms a hydrogel under the physiological condition through self‐assembly, and the peptide hydrogel exhibits injectability and adhesiveness to uterus, making it suitable for endometrial repair. Importantly, this hydrogel supports the adhesion and proliferation of UC‐MSCs in a 3D environment. In vivo experiments using rats with endometrial injury have shown that treatment with IVK8‐RGD hydrogel loaded with UC‐MSCs effectively restores endometrial thickness, inhibits fibrosis, and facilitates angiogenesis through activating Raf/MEK/ERK pathway, leading to significantly improved fertility and live birth rate. These findings demonstrate the potential of the UC‐MSCs‐loaded hydrogel in repairing damaged endometrium and may address the unmet clinical needs of treating recurrent miscarriage and infertility induced by endometrial damage.