Table 1. Effects of metabolic regulators on stem cell fate
Metabolic regulatorStem cell typeMethod of perturbationMain phenotypesReferences
FOXO transcription factorsESCsFOXO1 shRNA-mediated knockdown.Loss of pluripotency markers, spontaneous differentiation into mesoderm and endoderm lineages, impaired teratoma formation.(Zhang et al., 2011c)
ESCsFOXO4 shRNA-mediated knockdownReduced proteasome activity(Vilchez et al., 2012)
HSCsConditional FOXO1, 3 and 4 deletion in adult hematopoietic lineage.Premature depletion due to excessive proliferation, impaired self-renewal and increased apoptosis. High levels of ROS.(Tothova et al., 2007)
HSCsDeletion of FOXO3.Premature depletion due to impaired self-renewal and loss of quiescence. Myeloproliferative-like syndrome. High levels of ROS.(Miyamoto et al., 2007; Yalcin et al., 2008, Yalcin et al., 2010)
NSCsConditional FOXO1, 3, and 4 deletion in the brain.Premature depletion due to excessive proliferation, impaired self-renewal and increased apoptosis. High levels of ROS.(Paik et al., 2009)
NSCsDeletion of FOXO3.Premature depletion due to excessive proliferation, impaired self-renewal and increased apoptosis.(Renault et al., 2009)
Muscle stem cellsOverexpression of FOXO3.Decreased cell proliferation.(Rathbone et al., 2008)
Spermatogonial stem cellsConditional FOXO1, 3, and 4 deletion in male germ line.Increased cell death.(Goertz et al., 2011)
mTOR kinaseESCsDeletion of mTOR.Aborted embryonic development, impaired cell proliferation and small cell size.(Murakami et al., 2004)
ESCsshRNA-mediated knockdown of mTOR or inhibition by rapamycin.Decreased cell proliferation, loss of pluripotency markers, and increased mesoderm and endoderm differentiation.(Schieke et al., 2008; Zhou et al., 2009)
ESCsExpression of constitutively active S6 kinase 1 (target of mTOR).Increased differentiation.(Easley et al., 2010)
iPSCsInhibition by rapamycin.Increased reprogramming efficiency.(Chen et al., 2011)
iPSCsHyperactivation by TSC knockdown or knockout.Decreased reprogramming efficiency.(He et al., 2012)
HSCsHyperactivation of mTOR by deletion of TSC1 (negative regulator of mTOR).Loss of cellular quiescence, increased apoptosis, elevated mitochondrial biogenesis and ROS levels; defective hematopoiesis in transplant assays.(Gan et al., 2008; Chen et al., 2008)
HSCsInhibition by rapamycin (treatment of old mice).Rescue of age-related decline in self-renewal and hematopoiesis.(Chen et al., 2009)
NSCsHyperactivation of mTOR in dorsal telenchephalic neuroepithelium by deletion of TSC1 (negative regulator of mTOR).Abnormal CNS development due to transient increase in cell proliferation, followed by deregulated differentiation and neuronal migration.(Magri et al., 2011)
Epidermal stem cellsInhibition by rapamycin (treatment of Wnt1-overexpressing mice).Rescue of Wnt1-associated cellular senescence.(Castilho et al., 2009)
AMPKESCsActivation by AICAR.Decreased cell proliferation, loss of pluripotency markers and enhanced erythroid lineage differentiation.(Chae et al., 2012)
iPSCsActivation by metformin or A-769662.Decreased reprogramming efficiency.(Vazquez-Martin et al., 2012)
HSCsDeletion of α1 and α2 subunits of AMPK.Reduced numbers of HSCs but normal reconstitution capacity in transplant assays; decreased levels of ATP and mitochondrial DNA.(Nakada et al., 2010)
NSCsDeletion of β1 subunit of AMPK.Smaller brain size due to mitotic defects and increased apoptosis of differentiating progeny.(Dasgupta and Milbrandt, 2009)
SIRT1ESCsDeletion or knockdown of SIRT1.Largely normal but impaired DNA damage repair and apoptosis induction in response to oxidative stress.(McBurney et al., 2003; Han et al., 2008b; Oberdoerffer et al., 2008; Chae and Broxmeyer, 2011)
iPSCsActivation by reservatrol or fisetin.Increased reprogramming efficiency.(Chen et al., 2011)
HSCsDeletion of SIRT1.Normal hematopoiesis in adult mice despite increased proliferation, anemia and leukocytosis.(Narala et al., 2008; Leko et al., 2012)
HSCsDeletion of SIRT1.Impaired hematopoietic differentiation from embryoid bodies; decreased in vitro survival of progenitors cultured from adult mice.(Ou et al., 2011)
HSCsDeletion of SIRT1.Impaired self-renewal of embryonic HSCs.(Matsui et al., 2012)
NSCsDeletion or knockdown of SIRT1.Increased differentiation of astrocytes at the expense of neurons from embryonic NSCs cultured under oxidative conditions.(Prozorovski et al., 2008)
NSCsKnockdown or overexpression of SIRT1.Impaired neuronal differentiation upon knockdown; enhanced neuronal differentiation upon overexpression.(Hisahara et al., 2008)
Muscle stem cellsKnockdown or overexpression of SIRT1.Enhanced differentiation into myocytes upon knockdown; repressed differentiation into myocytes upon overexpression.(Fulco et al., 2003)
Muscle stem cellsOverexpression of SIRT1.Increased cell proliferation.(Rathbone et al., 2009)
Spermatogonial stem cellsDeletion of SIRT1.Reduced numbers probably due to increased levels of apoptosis; abnormal sperm differentiation.(McBurney et al., 2003; Coussens et al., 2008)