Mesenchymal stem cell extracellular vesicles ameliorate radiation-caused dry mouth via modulating immune balance and cell metabolism

Radiation therapy of head and neck cancers frequently leads to irreversible dry mouth that severely compromises the quality of life and is difficult to remedy. Mesenchymal stem cells (MSCs) could ameliorate this adverse effect, but their application is limited by high variations of conventional tissue-derived MSCs and many practical challenges of cell therapies. This study investigated the potential of extracellular vesicles (EVs) from standardized MSCs derived from iPS cells (iMSCs) in ameliorating radiation-caused dry mouth. In a mouse model, locally injected young but not aging iMSC-EVs after radiation preserved saliva secretion and acinar structures. Mechanistically, young iMSC-EVs reversed the acute inhibition of physiological inflammation and chronic increase of pathogenic inflammation in radiated salivary glands, which is related to the preservation of tissue-resident macrophages and polarization of infiltrated macrophages. At both acute and chronic phase after radiation, iMSC-EVs enhanced mitochondria-related cell metabolism pathways such as Oxidative Phosphorylation that modulate cell survival and macrophage polarization. OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination are much richer in effective young iMSC-EVs compared with inert aging EVs. Moreover, young iMSC-EV treatment increased hypusinated eIF5A in radiated salivary glands, especially in macrophages. These findings together indicated that iMSC-EVs are a promising cell-free product to restore salivary gland function impaired by radiation, which is mediated by maintaining immune balance and mitochondria-related cell metabolism at both acute and chronic phases.