Small Extracellular Vesicles From Human Amniotic Membrane Mesenchymal Stem Cells Rejuvenate Senescent beta Cells and Cure Age-Related Diabetes in Mice #MMPMID41391005
Xiao L; Zhang Z; Li T; Jiang Y; Liu Y; Lv T; Qin L; Zhu Y; Tang W
Aging Cell 2025[Dec]; ? (?): e70327 PMID41391005show ga
Targeting senescent pancreatic beta-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise beta-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve beta-cell integrity. We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of beta-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged beta-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed beta-cell functional decline by reducing senescent beta-cell populations, reinstating beta-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production. Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor alpha subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine 705 and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade. Our findings reveal hAMSC-sEVs as a novel senotherapeutic strategy for age-related diabetes, elucidating the pivotal role of miR-21-5p-driven epigenetic-mitochondrial calcium homeostasis in reversing beta-cell dysfunction, establishing a framework for targeting cellular senescence in metabolic disorders.
Aging+Cell 2025 ; ? (?): e70327
