An injectable hydrogel scaffold with IL-1β-activated MSC-derived exosomes for the treatment of endometritis

Chronic endometritis is a common gynecological disease resulting from various long-term recurrent infections, and is closely related to myositis, miscarriage, and even infertility. There is still no satisfactory treatment method currently in clinical therapy. Mesenchymal stem cell (MSC)-derived exosomes, an important kind of paracrine product, have been used to treat inflammatory diseases due to their promising immunomodulatory function and tissue repair ability similar to MSCs. Considering that the exosome contents and functions are regulated by the MSC status and the MSC status is significantly influenced by its surrounding microenvironment, we propose a hypothesis that exosomes derived from inflammation-simulated MSCs will possess stronger inhibition ability for inflammation. Herein, we used IL-1β to activate rat bone MSCs for obtaining β-exo and constructed an injectable polypeptide hydrogel scaffold by loading β-exo (β-exo@pep) for an in situ slow release of β-exo. The results showed that the polypeptide hydrogel can provide a sustained release of exosomes in 14 days. The β-exo@pep composite hydrogel can more effectively inhibit the production of inflammatory factors such as TNF-α, IL-1β, and IFN-γ, while it can promote the production of anti-inflammatory factors such as Arg-1, IL-6, and IL-10. The β-exo@pep composite hydrogel significantly promoted cell migration, invasion, and vessel tube formation in vitro. The experiments in a rat model of endometritis proved that the β-exo@pep composite scaffold possessed excellent ability towards anti-inflammation and endometrial regeneration. The research studies on the molecular mechanism revealed that the protein expressions of HMGB1 and phosphorylated IKB-α and p65 are down-regulated in the cells treated with β-exo@pep, indicating the involvement of the NF-κB signaling pathway. This study provides an effective method for the treatment of chronic endometritis, which is promising for clinical use.