, 2011). The regulation of telomerase activity is thus critical for the maintenance of stem cell function and tissue regenerative capacity. Stem cells must dynamically reprogram their cellular metabolism in response to changes in cell-cycle Osimertinib datasheet status, which can occur during normal development or after injury. The ways in which they change their metabolism are not yet understood but presumably involve activation of nutrient uptake and consumption, and changes in the biosynthetic pathways that support survival and proliferation (DeBerardinis et al., 2008 and Vander Heiden et al., 2009). Disruption of the mechanisms that

regulate these metabolic pathways can lead to profound defects in stem cells without necessarily having the same effects on restricted progenitors and differentiated cells (Gan et al., 2010, Gurumurthy et al., 2010 and Nakada et al., 2010). This suggests that some metabolic pathways are regulated differently in stem cells as compared to their progeny. Stem cells and their differentiated progeny have distinct metabolic

profiles. Cultured ES cells rely on glycolysis for ATP production but upregulate mitochondrial oxidative metabolism as they differentiate (Facucho-Oliveira and St John, 2009). Pluripotent cells in the inner cell mass also rely on glycolysis and upregulate oxidative metabolism during development (Facucho-Oliveira and St John, 2009). Highly proliferative, pluripotent cells therefore rely upon glycolysis for ATP production in vitro and in vivo, perhaps because glycolysis also yields substrates for anabolic biosynthetic pathways that UMI-77 proliferating cells depend upon (Vander Heiden et al., 2009). Adult HSCs Metalloexopeptidase have reduced concentrations of ATP and fewer mitochondria than differentiated cells and have been suggested to rely on glycolysis to generate ATP, even though these cells are mainly quiescent (Inoue et al., 2010, Kim et al., 1998 and Simsek et al., 2010). This raises the possibility that many undifferentiated stem cells preferentially rely upon glycolysis, irrespective of whether they

are highly proliferative or quiescent. Stem cells must coordinate energy metabolism with cell division. The PI-3kinase pathway is activated in response to various growth factors and promotes cell growth and proliferation, partly by activating Akt and mTORC1 (Figure 3) (Engelman et al., 2006). The Pten tumor suppressor negatively regulates PI-3kinase pathway signaling, and Pten deficiency increases cell growth and proliferation. Deletion of Pten increases the self-renewal of ES cells, as well as in vivo neurogenesis and in vitro self-renewal by CNS stem cells ( Gregorian et al., 2009, Groszer et al., 2006 and Groszer et al., 2001). In contrast, conditional Pten deletion from adult HSCs drives HSCs into cycle but quickly leads to their depletion by activating a tumor suppressor response marked by increased p16Ink4a and p53 expression ( Lee et al., 2010, Yilmaz et al., 2006 and Zhang et al.