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Войти в исследования International immunopharmacology · 2026
miR-671-5p-enriched exosomes derived from human embryonic stem cells under hypoxia balance oxidative stress homeostasis and macrophage reprogramming to alleviate Legg-Calvé-Perthes disease by targeting NOX2.
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Luo Tao, Liu Quan, Jiang Xiaohua, Zhou Tonghua, Jiang Shiding, Liu Gangan, Lan Xia
Аннотация
BACKGROUND: Legg-Calvé-Perthes disease (LCPD) remains a pediatric condition that causes hip joint deformities, with complicated pathogenesis. This study explored the influence of hypoxia-preconditioned human embryonic stem cells (hESCs)-derived exosomes on LCPD and its related mechanism.
METHODS: Spontaneously hypertensive rats (SHRs) and High mobility group B1 (HMGB1) -stimulated chondrocytes were used to mimic LCPD disease-like lesion in vivo and in vitro. Femoral head damage was examined by hematoxylin-eosin (HE) and Saffron-O and fast green staining. Target molecule expression was determined by real-time quantitative PCR (RT-qPCR), Western blotting, immunohistochemical staining, immunofluorescent staining, and enzyme-linked immunosorbent assay (ELISA). Mitochondrial dysfunction was analyzed by mitochondrial membrane potential and transition pore opening. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and BrdU incorporation. Molecular mechanisms were elucidated by dual luciferase reporter assay, m6A RNA immunoprecipitation (Me-RIP), and total RNA m6A level detection.
RESULTS: Hypoxia preconditioning observably elevated miR-671-5p level in hESCs and their exosomes. Methyltransferase-like 3 (METTL3)-mediated m6A crucially favored miR-671-5p biogenesis by DiGeorge syndrome critical region 8 (DGCR8) in hypoxia-exposed hESCs. Exosomes of hypoxia-exposed hESCs (Exohypoxia) delivered miR-671-5p to significantly attenuate HMGB1-induced oxidative stress injury, mitochondrial dysfunction, and pyroptosis of chondrocytes via targeting NADPH oxidase 2 (NOX2). Moreover, miR-671-5p-enriched Exohypoxia restrained macrophage inflammatory reprogramming via specifically inhibiting NOX2-mediated ROS accumulation. Exohypoxia ameliorated LCPD development in rats via modulation of miR-671-5p/NOX2 axis.
CONCLUSION: Exohypoxia transferred miR-671-5p to alleviate oxidative stress and pyroptosis of chondrocytes and M1 macrophage reprogramming via targeting NOX2, thereby ameliorating LCPD disease-like lesion.
METHODS: Spontaneously hypertensive rats (SHRs) and High mobility group B1 (HMGB1) -stimulated chondrocytes were used to mimic LCPD disease-like lesion in vivo and in vitro. Femoral head damage was examined by hematoxylin-eosin (HE) and Saffron-O and fast green staining. Target molecule expression was determined by real-time quantitative PCR (RT-qPCR), Western blotting, immunohistochemical staining, immunofluorescent staining, and enzyme-linked immunosorbent assay (ELISA). Mitochondrial dysfunction was analyzed by mitochondrial membrane potential and transition pore opening. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and BrdU incorporation. Molecular mechanisms were elucidated by dual luciferase reporter assay, m6A RNA immunoprecipitation (Me-RIP), and total RNA m6A level detection.
RESULTS: Hypoxia preconditioning observably elevated miR-671-5p level in hESCs and their exosomes. Methyltransferase-like 3 (METTL3)-mediated m6A crucially favored miR-671-5p biogenesis by DiGeorge syndrome critical region 8 (DGCR8) in hypoxia-exposed hESCs. Exosomes of hypoxia-exposed hESCs (Exohypoxia) delivered miR-671-5p to significantly attenuate HMGB1-induced oxidative stress injury, mitochondrial dysfunction, and pyroptosis of chondrocytes via targeting NADPH oxidase 2 (NOX2). Moreover, miR-671-5p-enriched Exohypoxia restrained macrophage inflammatory reprogramming via specifically inhibiting NOX2-mediated ROS accumulation. Exohypoxia ameliorated LCPD development in rats via modulation of miR-671-5p/NOX2 axis.
CONCLUSION: Exohypoxia transferred miR-671-5p to alleviate oxidative stress and pyroptosis of chondrocytes and M1 macrophage reprogramming via targeting NOX2, thereby ameliorating LCPD disease-like lesion.