Effects of oxidative stress on mouse embryonic stem cell proliferation, apoptosis, senescence, and self-renewal.

Oxidative stress, associated with either normal metabolism or disease conditions, affects many cellular activities. Most of our knowledge in this field is derived from fully differentiated cells. Embryonic stem cells (ESCs) have attracted enormous attention for their potential applications in cell therapy, but little is known about how the unique properties of ESCs are affected by oxidative stress. We have investigated the effects of oxidative stress induced by H(2)O(2) on several cellular activities of mouse ESCs. Like differentiated cells, ESCs are sensitive to H(2)O(2)-induced apoptosis when continuously exposed to H(2)O(2) at the concentrations above 150 microM. However, unlike differentiated cells, ESCs are resistant to oxidative stress induced senescence. This is demonstrated by the results that when subjected to a short-term sublethal concentration and duration of H(2)O(2) treatment, fibroblasts enter the senescent state with enlarged flattened cell morphology concurrent with increased expression of senescence marker p21. On the contrary, ESCs neither show any sign of senescence nor express p21. Instead, ESCs enter a transient cell cycle arrest state, but they have remarkable recovery capacity to resume the normal cell proliferation rate without losing the ability of self-renewal and pluripotency. Our results further revealed that H(2)O(2) inhibits cell adhesion and the expression of cyclin D1, which are early events proceeding apoptosis and cell cycle arrest. In conclusion, our data suggest that ESCs are sensitive to H(2)O(2) toxicity, but may have unique mechanisms that prevent H(2)O(2)-induced senescence and protect self-renewal capacity.