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Ectopic endometrial mesenchymal stem cells derived exosomal miR-4466 promotes angiogenesis by targeting RUNX1 in adenomyosis.

ABSTRACT: Background Abnormal angiogenesis plays a crucial role in the pathogenesis of adenomyosis (AM). Emerging evidence suggests exosomes derived from endometrial cells can boost AM progression. In this study, we aim to investigate the pro-angiogenic role and potential mechanisms of ectopic endometrial mesenchymal stem cells (eMSCs) derived exosomes (Ec-eMSCs-Exos) in adenomyotic lesions. Methods MicroRNA sequencing (miRNA-Seq) was conducted to identify differentially expressed miRNAs (DE miRNAs) in normal eMSCs derived exosomes (N-eMSCs-Exos) and Ec-eMSCs-Exos. Candidate miRNAs were selected using quantitative real-time polymerase chain reaction (qRT-PCR). The cell internalization assay were performed to confirm the internalization of exosomal miR-4466 into recipient human umbilical vein endothelial cells (HUVECs). The effects of exosomal miR-4466 on HUVEC proliferation, invasion/migration, and tube formation were analyzed in vitro using CCK8, EdU, transwell, wound healing, and μ-slide angiogenesis assays. The target gene of miR-4466 was predicted through bioinformatics analysis and further verified by qRT-PCR, western blot, dual luciferase reporter assay and rescue experiment. Results We identified 81 up-regulated and 92 down-regulated miRNAs between N-eMSCs-Exos and Ec-eMSCs-Exos. Among these DE miRNAs, miRNA-4466 was the most significantly up-regulated. The internalization assay showed that exosomal miR-4466 can be internalized by HUVECs. Overexpression or inhibition of miR-4466 can significantly promote or inhibit the proliferation, invasion/migration, and tube formation of HUVECs in vitro. By using bioinformatics predictions and luciferase reporter assay, we found that runt-related transcription factor 1 (RUNX1) was a direct targrt of miR-4466. Moreover, rescue experiment confirmed that RUNX1 overexpression reversed the pro-angiogenic effect of miR-4466 by inhibiting VEGFA expression. Conclusion Ectopic eMSCs derived exosomal miR-4466 promotes angiogenesis by targeting the RUNX1/VEGFA axis in AM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261030 | GEO | 2026/02/04

REPOSITORIES: GEO

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Project description:Rationale：Poor peri-implant osseointegration of dental implants in patients with type II diabetes has become a major clinical challenge in recent years. MSC (Mesenchymal stem cell)-derived exosomes may play an important role in peri-implant osseointegration, but the mechanism remains unclear. Enhancing the therapeutic effect of MSC-derived exosomes and exploring the potential mechanism can help provide a new therapeutic strategy to improve the clinical outcome of dental implant restorations in patients with type II diabetes. Methods：The exosomes derived from hypoxia (Hypo-exos) or normoxia (Nor-exos) preconditioned bone marrow mesenchymal stem cells (BMSCs) were co-cultured with BMSCs and human umbilical vein endothelial cells (HUVECs). The effect of exosomes on BMSCs cell proliferation was detected by CCK-8 assay and EdU assay, and the effect on angiogenesis ability of HUVECs was detected by wound healing assay, transwell migration assay, tube formation assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. A diabetic rat dental implant model was also established and the effect of exosomes on implant osseointegration was evaluated through micro-CT scanning and histological analysis. The differentially expressed miRNAs between Hypo-exos and Nor-exos were identified by high-throughput miRNA sequencing. Subsequently, the target genes and their roles in regulating angiogenesis were predicted and analyzed by bioinformatics analysis and dual luciferase reporter assay. Results：In vitro experiments indicated that hypoxia preconditioning could elevate exosome production and promote cell proliferation of BMSCs and angiogenesis of HUVECs. Moreover, Hypo-exos promoted peri-implant osteogenesis in rats with diabetes. Further investigation revealed the vital involvement of the miR-106b-5p/HIF-1α axis in promoting peri-implant osseointegration. Conclusion: Exosomes derived from hypoxia-preconditioned BMSCs could improve the peri-implant osseointegration in rats with diabetes by promoting cell proliferation and angiogenesis, and the miR-106b-5p/ HIF-1α axis could be the underlying mechanism.

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Ectopic endometrial mesenchymal stem cells derived exosomal miR-4466 promotes angiogenesis by targeting RUNX1 in adenomyosis.

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