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MSC mediate numerous therapeutic effects by promoting repair directly via differentiation into critical cell types or indirectly through the secretion of a broad spectrum of soluble factors with diverse paracrine activities. However, recent discoveries indicate that MSC are sensitive to endogenous and exogenous stressors and many diseaserelated interventions can result in Therapy-Induced Senescence (TIS) in MSC. Here, we provide a detailed analysis of changes in secretory factors that occur under conditions of bleomycin treatment that triggers genotoxic stressinduced senescence of Human Adipose-Derived Stem Cells (hADSCs). The bleomycin treatment considerably alters the composition of hADSCs secretome. Our data reveal the novel unique composition of Senescence Messaging Secretome (SMS) of hADSCs and suggest that this SMS might critically influence genotoxic drug-based or MSC combinational therapies by imposing interference with tissue homeostasis, metabolism and regeneration in autocrine and paracrine fashion. SMS can compromise MSC-mediated immunological responses and their regenerative potential. Our findings underscore the importance of careful evaluation of stress-induced senescence of adult stem cells in regenerative and combination therapies.

Acute Genotoxic Stress-Induced Senescence in Human Mesenchymal Cells Drives a Unique Composition of Senescence Messaging Secretome (SMS)