Cell Stem Cell
Metabolic Regulation in Pluripotent Stem Cells
during Reprogramming and Self-Renewal
Jin Zhang,1,11,12Esther Nuebel,2,11George Q. Daley,5,6,7,8,9,10Carla M. Koehler,2,3and Michael A. Teitell1,3,4,*
1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine
2Department of Chemistry and Biochemistry
3Molecular Biology Institute
4Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center, and California NanoSystems Institute
University of California, Los Angeles, Los Angeles, CA 90095, USA
5Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research
6Howard Hughes Medical Institute
Children’s Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA
7Division of Hematology, Brigham and Women’s Hospital, Boston, MA 02115, USA
8Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
9Broad Institute, Cambridge, MA 02142, USA
10Harvard Stem Cell Institute, Cambridge, MA 02138, USA
11These authors contributed equally to this work
12Present address: Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Small, rapidly dividing pluripotent stem cells (PSCs) have unique energetic and biosynthetic demands
compared with typically larger, quiescent differentiated cells. Shifts between glycolysis and oxidative phos-
phorylation with PSC differentiation or reprogramming to pluripotency are accompanied by changes in cell
cycle, biomass, metabolite levels, and redox state. PSC and cancer cell metabolism are overtly similar,
with metabolite levels influencing epigenetic/genetic programs. Here, we discuss the emerging roles for
metabolism in PSC self-renewal, differentiation, and reprogramming.
Pluripotent stem cells (PSCs), including embryonic stem cells
(ESCs) and induced pluripotent stem cells (iPSCs), have an
unlimited capacity for self-renewal and can differentiate into
every cell type in our bodies, which holds significant promise
for applications in regenerative medicine. Cellular features of
‘‘stemness’’ and underlying genetic and epigenetic mechanisms
that control self-renewal, differentiation, and reprogramming are
being intensely studied (Boyer et al., 2005; Orkin and Hochedlin-
ger, 2011). Rapidly increasing attention is also being directed
toward the roles for metabolism in PSCs. In contrast to differen-
tiated cells, PSCs have a short G1 phase of the cell cycle, during
which most biomass accumulation and differentiation occurs,
limiting PSC growth and differentiation potential (Singh and
Dalton, 2009; Wang et al., 2008). To facilitate rapid cell duplica-
tion, PSCs must balance energetic with biosynthetic demands,
a feature shared with highly proliferative cancer cells. In general,
ATP is produced by glycolysis and oxidative phosphorylation
(OXPHOS), while the synthesis of lipids, nucleotides, and
proteins requires nutrient uptake, processing, and internal
metabolite precursor entry into multiple anabolic pathways
(DeBerardinis et al., 2008). Key differences in metabolism
between PSCs and differentiated cells exist, in contrast to
striking similarities in metabolism between PSCs and cancer
ences chromatin organization and transcription (Dang, 2012;
Ward and Thompson, 2012), which likely also occurs in PSCs
tocontrol physiologyandfate. Here,toaccompany thePerspec-
tive in this issue of Cell Stem Cell by Folmes et al. (2012), we
provide a perspective on the current state of PSC metabolism,
which includes consideration of energetics, multiple nutrient
and carbon sources, and oxidation-reduction (redox) states in
the context of early mammalian development, adult-type stem
cells, and cancer. We also examine emerging links between
selected signal transduction pathways, PSC metabolism, and
genetic and epigenetic regulatory networks. Of note, the modest
extensive studies in cancer, which has led to gap-filling assump-
tions for PSCs based on similar studies in cancer that should be
Energetics of Pluripotency
OXPHOS can theoretically generate up to 38 mol ATP per mol
glucose (depending on NADH shuttling into mitochondria and
electron transport chain [ETC] coupling efficiency), whereas
glycolysis generates only 2 mol ATP per mol glucose. Yet,
numerous studiesshow thatmouse and human ESCs and iPSCs
have an elevated dependence on glycolysis under aerobic
conditions compared to highly respiring (e.g., cardiomyocytes)
or lowly respiring (e.g., fibroblasts) differentiated cell types
(Chung et al., 2007; Folmes et al., 2011; Panopoulos et al.,
2012; Prigione et al., 2010; Varum et al., 2011; Zhang et al.,
2011). In cancer, a high glycolytic flux provides sufficient ATP
and anabolic precursors for rapid proliferation, with the pentose
phosphate pathway generating ribose-5-phosphate for nucleo-
tides and NADPH-reducing power for nucleotide and lipid
biosynthesis (DeBerardinis et al., 2008; Locasale and Cantley,
2011). Human PSCs also have a high glycolytic flux (Prigione
et al., 2010) and mouse ESCs require increased pentose phos-
phate pathway activity for survival during oxidative stress and
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Cell Stem Cell