| Summary: | Oxidative stress induces cellular damage, which accelerates aging and promotes the development of serious illnesses. Adipose-derived stem cells (ADSCs) are novel cellular therapeutic tools and have been applied for tissue regeneration. However, ADSCs from aged and diseased individuals may be affected in vivo by the accumulation of free radicals, which can impair their therapeutic efficacy. Substance-P (SP) is a neuropeptide that is known to rescue stem cells from senescence and inflammatory attack, and this study explored the restorative effect of SP on ADSCs under oxidative stress. ADSCs were transiently exposed to H<sub>2</sub>O<sub>2</sub>, and then treated with SP. H<sub>2</sub>O<sub>2</sub> treatment decreased ADSC cell viability, proliferation, and cytokine production and this activity was not recovered even after the removal of H<sub>2</sub>O<sub>2</sub>. However, the addition of SP increased cell viability and restored paracrine potential, leading to the accelerated repopulation of ADSCs injured by H<sub>2</sub>O<sub>2</sub>. Furthermore, SP was capable of activating Akt/GSK-3β signaling, which was found to be downregulated following H<sub>2</sub>O<sub>2</sub> treatment. This might contribute to the restorative effect of SP on injured ADSCs. Collectively, SP can protect ADSCs from oxidant-induced cell damage, possibly by activating Akt/GSK-3β signaling in ADSCs. This study supports the possibility that SP can recover cell activity from oxidative stress-induced dysfunction.
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