circPTP4A2-miR-330-5p-PDK2 Signaling Facilitates In Vivo Survival of HuMSCs on SF-SIS Scaffolds and Improves The Repair of Damaged Endometrium

Background Human umbilical cord MSCs (HuMSC)-based therapy has shown promising results in the treatment of intrauterine adhesions (lUA). In this study, our aim was to construct a HuMSC-seeded silk fibroin small-intestinal submucosa (SF-SIS) scaffold and evaluate the impact of repairing the damaged endometrium in an lUA mouse model. Methods To identify the functional effect of HuMSCs-silk cellulose (SF)- small-intestinal submucosa (SIS) scaffolds on the repair of damaged endometrium, a mouse lUA model was established in this study. The uterine morphology and fibrosis were evaluated by hematoxylin - eosin (H&E) staining and Masson staining. CircRNA sequencing, real-time PCR and RNA fluorescence in situ hybridization were used to screen and verify the potential circRNAs that involved in the repair of damaged endometrium by HuMSCs. Real time integrated cellular oxygen consumption rate (OCR) was measured using the Seahorse XF24 Extracellular Flux Analyser. The potential down-stream miRNAs and proteins of circRNAs were analyzed dual-luciferase report and Western Blot. Results We found that HuMSCs-SF-SIS not only increased the number of glands, but also reduced the ulcer area in the IUA model. Furthermore, we demonstrated that circPTP4A2 was elevated in the HuMSCs seeded on the SF-SIS scaffolds and stabilized the mitochondrial metabolism through miR-330-5p-PDK2 signaling, which contributes to endometrial repair progression. Conclusion In this study, we demonstrated that circPTP4A2 was elevated in the HuMSCs seeded on the SF-SIS scaffolds and stabilized the mitochondrial metabolism through miR-330-5p-PDK2 signaling, which contributes to endometrial repair progression. These findings demonstrate that HuMSC-seeded SF-SIS scaffolds are an encouraging method for the treatment of lUA.