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Arsenic exposure through contaminated food, water, and air causes irreversible neural damage and affects millions of people worldwide. Several studies have demonstrated that the secreted factors (secretome) from mesenchymal stromal/stem cells (MSCs) can promote neural recovery after several forms of injury including stroke and neurodegenerative diseases. The present study was conducted to determine if the secretome from adipose-derived MSCs (ADSCs) prevents arsenic damage to SH-SY5Y cells. To this end, human neuroblastoma cells (SH-SY5Y) were pre-treated with the secretome from ADSCs and then challenged with different concentrations of arsenic. After various doses and exposure times, the extent of neuronal injury was assessed using MTT reduction and LDH release assays as well as LIVE/DEAD staining. These data demonstrate that the ADSC secretome protects SH-SY5Y cells from arsenic-induced toxicity. Previous reports have shown that the secretome of MSCs can induce neuroblast differentiation and mature neurons are less susceptible to chemical-induced toxicity. In the current study, proliferation assays, neurite length assessment, and quantitative RT-PCR of differentiation markers indicated that the ADSC secretome does not induce SH-SY5Y differentiation into a mature neuron-like phenotype. In contrast, our results demonstrated that soluble factor(s) in the ADSC secretome enhance SH-SY5Y cell substrate-dependent adhesion. The present study is the first to illustrate that the secretome from ADSCs protects SH-SY5Y cells from arsenic-induced toxicity. Additionally, we showed that protection against arsenic toxicity is not dependent on SH-SY5Y cell differentiation into a mature neuron-like phenotype, but involves soluble factor(s) in the secretome that appear to enhance cell survival by an adhesion-dependent mechanism.The adipose-derived stem cell (ADSC) secretome protects SH-SY5Y cells from arsenic-induced toxicity.Neurotoxin protection conferred by the ADSC secretome uses a differentiation-independent mechanism.Soluble factor(s) from the secretome enhance SH-SY5Y cell adhesion potentially leading to protection against arsenic-induced toxicity.