Exposure of human diploid fibroblasts to hypoxia extends proliferative life span

Normal human mitotic cells do not proliferate indefinitely in culture but undergo a limited number of divisions and progressively reach a state of irreversible growth arrest, a process termed replicative senescence. Hypoxia is a situation of reduced oxygen concentration that relates to many physiological and pathophysiological conditions. In the current study we investigated the effects of oxygen concentration, in both normoxic and hypoxic conditions, on the proliferative capacity, cell viability, oxidative status, and protein expression of human embryonic diploid fibroblasts. Maintenance of WI38 and IMR90 cells in 1.5% or 3% O(2) concentration significantly delayed the appearance of replicative senescence compared to cells grown in 20% O(2), induced the hypoxia-inducible factor-1alpha, and resulted in reduced expression levels of the key cell cycle modulators, namely p21 and p16. Moreover, cell exposure to short-term hypoxia affected their response to several cytotoxic agents, whereas adaptation to the hypoxic environment prior to the treatment had no impact on cell viability. These findings clearly identify that oxygen concentration plays a crucial role in regulating cellular life span of normal human cells.