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Objective: Skeletal tissues such as intervertebral disc and articular cartilage possess limited innate potential to regenerate, in part due to their avascularity and low cell density. Despite recent advances in mesenchymal stem cell (MSC)-based disc and cartilage regeneration, key challenges remain, including the sensitivity of these cells to in vivo microenvironmental stress such as low oxygen and limited nutrition. The objective of this study was to investigate whether preconditioning with hypoxia and/or transforming growth factor-β 3 (TGF-β3) can enhance MSC survival and extracellular matrix production in a low oxygen and nutrient-limited microenvironment., Design: MSCs from multiple bovine donors were preconditioned in monolayer in normoxia or hypoxia, with or without TGF-β3, and the global effects on gene expression were examined using microarrays. Subsequently, the effects of preconditioning on MSC survival and extracellular matrix production were examined using low oxygen and nutrient-limited pellet culture experiments., Results: Hypoxic preconditioning resulted in upregulation of genes associated with growth, cell-cell signaling, metabolism, and cell stress response pathways, and significantly enhanced MSC survival for all donors in low oxygen and nutrient-limited pellet culture. In contrast, TGF-β3 preconditioning diminished survival. The nature and magnitude of the effects of preconditioning with either hypoxia or TGF-β3 on glycosaminoglycan production were donor dependent., Conclusions: These results strongly support the use of hypoxic preconditioning to improve postimplantation MSC survival in avascular tissues such as disc and cartilage.