Human embryonic stem cells: mechanisms to escape replicative senescence?

Human embryonic stem cells (hESCs) are unique in that they can proliferate indefinitely in culture in an undifferentiated state as well as differentiate into any somatic cells. Undifferentiated hESCs do not appear to undergo senescence and remain nontransformed over multiple passages. Culture hESCs maintain telomere length and exhibit high telomerase activity after prolonged in vitro culture. The ability of hESCs to bypass senescence is lost as hESCs differentiate into fully differentiated somatic cells. This loss of immortality upon differentiation may be due to a variety aging related factors such as reduction in telomere length, alteration of telomerase activity, changes in cell cycle regulation and decrease in DNA repair ability. Absence of such aging factors as well as the lack of genomic, mitochondrial and epigenetic changes, may contribute to the lack of senescence in hESCs. In this review, we will summarize recent advances in determining changes in these aspects in prolonged hESC cultures. We will in particular discuss the potential roles of several cellular pathways including the telomerase, p53, and Rb pathways in escaping senescence in hESCs. We will also discuss the genomic and epigenetic changes in long-term hESC culture and their potential roles in bypassing senescence, as well as alternative sources of pluripotent stem cells.