, 2009 and Tothova et al., 2007). Treating FoxO-deficient mice with the antioxidant N-acetyl-L-cysteine partially rescues these stem cell defects. FoxO3 appears to be the most important FoxO for stem cell function, because deletion of FoxO3 alone also depletes CNS stem cells and HSCs ( Miyamoto et al., 2007, Renault

et al., 2009 and Yalcin et al., 2008). In contrast to HSCs, FoxO-deficient restricted myeloid progenitors do not exhibit increased ROS levels ( Tothova et al., 2007). This suggests that stem cells depend more upon FoxO transcription factors than certain downstream progenitors. Prdm16 is another transcription factor that promotes stem cell maintenance in multiple tissues, at least partly by regulating oxidative stress (Figure 3). Prdm16 is a zinc finger protein that was originally identified as part of a chromosomal translocation in some human acute myeloid leukemias (Morishita, 2007). Consistent with this, overexpression Vemurafenib concentration Selleckchem PD332991 of the Prdm16 proto-oncogene can immortalize myeloid cells (Nishikata et al., 2003); however, the physiological role of Prdm16 is to regulate stem cell function in multiple tissues. Prdm16 is necessary for the development of brown fat cells (Seale et al., 2008), as well as for the maintenance of stem

cell activity in the nervous and hematopoietic systems (Chuikov et al., 2010). The depletion of neural stem cells is at least partially due to increased oxidative stress, because the depletion can be partially rescued by treatment with N-acetyl-L-cysteine. Prdm16 appears to regulate mitochondrial function and to prevent the accumulation of ROS, though the mechanisms by which this occurs remain unknown. The polycomb protein Bmi-1 promotes stem cell maintenance by negatively regulating p16Ink4a and p19Arf expression

( Bruggeman et al., 2005, Jacobs et al., 1999, Molofsky et al., 2005 and Oguro et al., 2006) and likely by regulating mitochondrial function and oxidative stress as well ( Figure 3) ( Liu et al., 2009). Cells from Bmi1-deficient mice have reduced mitochondrial oxygen consumption, reduced mitochondrial oxidative capacity, reduced ATP levels, and elevated ROS levels that appear to cause DNA damage ( Liu et al., 2009). Treating Bmi1-deficient mice with N-acetyl-L-cysteine partially rescues the depletion of thymocytes, though it has not yet been tested whether this second also rescues stem cell function. The observation that Bmi-1 regulates tumor suppressor expression and mitochondrial function suggests that key self-renewal mechanisms integrate energy metabolism with cell-cycle control in a manner analogous to PI-3kinase pathway regulation by Pten, AMPK, and Lkb1. Although elevated ROS levels are toxic to stem cells, physiological levels of ROS are required for certain stem cell functions. Consistent with the role of Akt in negatively regulating FoxO function (Salih and Brunet, 2008), deletion of Akt1 and Akt2 decreases ROS levels and attenuates the proliferation and differentiation of HSCs ( Juntilla et al.