Simulated Microgravity Induced Mesenchymal Stem Cell Senescence via the Activation of Cytosolic mtDNA-cGAS-STING Axis

Microgravity brings various pathological changes to astronauts, which may be related to the senescence of adult stem cells. However, how microgravity affects the senescence of stem cells remains barely known. In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence. Rotating culture also promoted the cytosolic leakage of mitochondrial DNA (mtDNA), while the depletion of mtDNA inhibited cGAS-STING activation and reversed MSC senescence. Knockdown of either BAK or BAX, proteins forming pores on the mitochondrial outer membrane, suppressed mtDNA leakage, cGAS-STING activation, and MSC senescence, suggesting that BAK/BAX mediates the activation of mtDNA-cGAS-STING axis and the associated MSC senescence. Recovering mitochondrial function by Mito TEMPO inhibited the activation of mtDNA-cGAS-STING axis and reversed MSC senescence. In vivo, using rat hindlimb unloading (HU) model to simulate microgravity, it was found that inhibition of STING ameliorated MSC senescence induced by HU. Together, our study demonstrated that simulated microgravity induces MSC senescence by the activation of cytosolic mtDNA-cGAS-STING axis and indicated cGAS-STING pathway as a therapeutic target of MSC senescence under microgravity.