Metabolic Plasticity in Stem Cell Homeostasis and Differentiation
2012; Elsevier BV; Volume: 11; Issue: 5 Linguagem: Inglês
10.1016/j.stem.2012.10.002
ISSN1934-5909
AutoresClifford D.L. Folmes, Petras P. Dzeja, Timothy J. Nelson, André Terzic,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoPlasticity in energy metabolism allows stem cells to match the divergent demands of self-renewal and lineage specification. Beyond a role in energetic support, new evidence implicates nutrient-responsive metabolites as mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. Stem cell metabolism also offers a potential target for controlling tissue homeostasis and regeneration in aging and disease. In this Perspective, we cover recent progress establishing an emerging relationship between stem cell metabolism and cell fate control. Plasticity in energy metabolism allows stem cells to match the divergent demands of self-renewal and lineage specification. Beyond a role in energetic support, new evidence implicates nutrient-responsive metabolites as mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. Stem cell metabolism also offers a potential target for controlling tissue homeostasis and regeneration in aging and disease. In this Perspective, we cover recent progress establishing an emerging relationship between stem cell metabolism and cell fate control. Metabolism (from the Greek μεταβoλη´, i.e., transition, transformation) supports fundamental processes throughout life, as cells require a continuous yet adaptable energy supply to meet the demands of their specialized functions. Metabolic flexibility fuels divergent stem cell fates, which include quiescence to minimize stress damage, proliferation and self-renewal to maintain progenitor pools, and lineage specification for tissue regeneration. These vital processes are powered through the metabolism of energy substrates supplied by the environment, such as glucose, fatty acids, and amino acids. Catabolism, the process of breaking down (oxidizing) metabolites to produce energy, and anabolism, the process of constructing macromolecules from precursors, are tightly balanced. As a result, catabolic products, including hydrocarbons and energy in the form of ATP and reducing cofactors, serve as substrates for the anabolic production of macromolecules that cannot be obtained from the environment. Beyond providing energetic supply, metabolic circuits engage master genetic programs in control of cell behavior (McKnight, 2010McKnight S.L. On getting there from here.Science. 2010; 330: 1338-1339Crossref PubMed Scopus (86) Google Scholar), with cellular identity and functional state reflecting the specific metabolic pathways being used. This Perspective highlights the plasticity in stem cell metabolism, which enables prioritization of metabolic pathways to match anabolic and catabolic demands of evolving identities during cell fate determination. The one-cell embryo preferentially metabolizes pyruvate over glucose, extending the metabolic pattern of the oocyte (Figure 1). Initial oxidative metabolism in the embryo relies on abundant maternal mitochondria inherited from the oocyte. Early cell divisions in the preimplantation embryo result in discrete mitochondrial segregation, leading to reduced mitochondrial DNA copy number and density, as replication is initiated after implantation. This yields populations of progenitor cells with a spectrum of heteroplasmy, or mixture of healthy and mutated mitochondrial DNA (mtDNA). Mitochondrial patterning allows blastomeres to purge metabolism-deficient progeny harboring disproportionally high levels of maternally derived mutant mtDNA, thus selecting for healthy metabolic profiles and preventing mutational meltdown in subsequent generations (Fan et al., 2008Fan W. Waymire K.G. Narula N. Li P. Rocher C. Coskun P.E. Vannan M.A. Narula J. Macgregor G.R. Wallace D.C. 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Patel M.S. Intermediary metabolism and energetics during murine early embryogenesis.J. Biol. Chem. 2003; 278: 31457-31460Crossref PubMed Scopus (50) Google Scholar). Priming of the glycolytic system may occur in anticipation of implantation into the hypoxic uterine wall, as glucose uptake is further accelerated following implantation, where virtually all glucose is metabolized to lactate. During later development, mitochondrial replication, maturation into tubular cristae-dense structures, and cytosolic deployment enables reinitiation of oxidative metabolism and progressive decline in glycolysis (Johnson et al., 2003Johnson M.T. Mahmood S. Patel M.S. Intermediary metabolism and energetics during murine early embryogenesis.J. Biol. Chem. 2003; 278: 31457-31460Crossref PubMed Scopus (50) Google Scholar; Van Blerkom, 2009Van Blerkom J. Mitochondria in early mammalian development.Semin. Cell Dev. Biol. 2009; 20: 354-364Crossref PubMed Scopus (134) Google Scholar). The chronology of metabolic regimes is underscored by embryonic phenotypes that reflect disrupted metabolic processes (Johnson et al., 2003Johnson M.T. Mahmood S. Patel M.S. Intermediary metabolism and energetics during murine early embryogenesis.J. Biol. Chem. 2003; 278: 31457-31460Crossref PubMed Scopus (50) Google Scholar). Glycolytic gene mutations precipitate early postimplantation lethality, while defects in oxidative processes, such as pyruvate dehydrogenase mutations or genetic disruption of the mitochondrial transcription factor TFAM, result in developmental delay and/or late onset lethality (Johnson et al., 2003Johnson M.T. Mahmood S. Patel M.S. Intermediary metabolism and energetics during murine early embryogenesis.J. Biol. Chem. 2003; 278: 31457-31460Crossref PubMed Scopus (50) Google Scholar; Larsson et al., 1998Larsson N.G. Wang J. Wilhelmsson H. Oldfors A. Rustin P. Lewandoski M. Barsh G.S. Clayton D.A. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice.Nat. Genet. 1998; 18: 231-236Crossref PubMed Scopus (1192) Google Scholar). The maturation of more efficient metabolic infrastructure during development has also been documented in highly specialized tissues. Cardiomyocytes from day 9.5 embryos (e9.5) contain few fragmented mitochondria with poorly defined and unorganized cristae, similar to those in the early embryo, which undergo extensive maturation into filamentous networks of elongated and branched mitochondria with abundant and organized cristae by day e13.5 (Hom et al., 2011Hom J.R. Quintanilla R.A. Hoffman D.L. de Mesy Bentley K.L. Molkentin J.D. Sheu S.S. Porter Jr., G.A. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation.Dev. Cell. 2011; 21: 469-478Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Cardiomyocyte development is dependent on mitochondrial status, as early induction of mitochondrial maturation accelerates cardiomyocyte differentiation, while differentiation is impaired when mitochondria are arrested in the immature state (Folmes et al., 2012bFolmes C.D.L. Dzeja P.P. Nelson T.J. Terzic A. Mitochondria in control of cell fate.Circ. Res. 2012; 110: 526-529Crossref PubMed Scopus (65) Google Scholar; Hom et al., 2011Hom J.R. Quintanilla R.A. Hoffman D.L. de Mesy Bentley K.L. Molkentin J.D. Sheu S.S. Porter Jr., G.A. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation.Dev. Cell. 2011; 21: 469-478Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Progenitors in the developing retina are dependent on glycolytic flux from endogenous stores, such as glycogen, for proliferation and survival, while forced differentiation switches glycolysis into oxidative metabolism for ATP generation (Agathocleous et al., 2012Agathocleous M. Love N.K. Randlett O. Harris J.J. Liu J. Murray A.J. Harris W.A. Metabolic differentiation in the embryonic retina.Nat. Cell Biol. 2012; 14: 859-864Crossref PubMed Scopus (117) Google Scholar). Metabolic plasticity thus enables flexibility in energetic substrate choice, which is critical for proper development. Different cell states require specific metabolic programs to support the unique bioenergetic demands underlying their specialized functions. Flexibility in metabolic pathway utilization maintains a balance of anabolic processes to support synthesis of cellular building blocks, and catabolic processes to ensure adequate bioenergetic resources. Metabolic requirements are defined by the energetic demands of stem cell proliferation, lineage specification, and quiescence. As such, metabolism at a stemness ground state is unable to fulfill the needs of differentiated progeny. Conversely, metabolic metamorphosis underlies pluripotent induction during nuclear reprogramming. Proliferating cells have a high requirement for not only reducing cofactors (NADPH) and energy (ATP), but also carbon, nitrogen, and hydrogen to support biosynthesis of cell building blocks required for replication (Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10144) Google Scholar; Zhang et al., 2012Zhang J. Nuebel E. Daley G.Q. Koehler C.M. Teitell M.A. Metabolism in pluripotent stem cell self-renewal, differentiation, and reprogramming.Cell Stem Cell. 2012; 11 (this issue): 589-595Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar in this issue of Cell Stem Cell). Complete consumption of available substrates cannot support their anabolic requirements. Rather, partial breakdown of glucose through glycolysis and shunting of intermediates through the pentose phosphate pathway provide a compromise between catabolic generation of ATP and reducing cofactors, and production of biosynthetic substrates to meet anabolic requirements (Figure 2). Indeed, increased expression of glycolytic enzymes and stimulation of glycolysis is required for cell immortalization and is sufficient to increase cellular lifespan (Kondoh et al., 2005Kondoh H. Lleonart M.E. Gil J. Wang J. Degan P. Peters G. Martinez D. Carnero A. Beach D. Glycolytic enzymes can modulate cellular life span.Cancer Res. 2005; 65: 177-185PubMed Google Scholar). Although glycolysis is inherently less efficient, producing a fraction of ATP compared to oxidative consumption of glucose, glycolysis does enable a fast rate of energy generation. Under abundant supply of glucose, the percentage of ATP generated from glycolysis can surpass that produced by oxygen-dependent respiration (Guppy et al., 1993Guppy M. Greiner E. Brand K. The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes.Eur. J. Biochem. 1993; 212: 95-99Crossref PubMed Scopus (170) Google Scholar). As such, mitochondria may redirect away from oxidative ATP generation to cataplerosis, enabling extraction of partially oxidized substrates from the tricarboxylic acid (TCA) cycle for biosynthetic purposes. Similar to the early embryo, embryonic stem cells (ESCs) have a low mtDNA copy number and harbor a sparse mitochondrial infrastructure with immature cristae and limited perinuclear localization (Chung et al., 2007Chung S. Dzeja P.P. Faustino R.S. Perez-Terzic C. Behfar A. Terzic A. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells.Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: S60-S67Crossref PubMed Scopus (384) Google Scholar). Such mitochondrial infrastructure is also characteristic of hematopoietic stem cells (HSCs) (Piccoli et al., 2005Piccoli C. Ria R. Scrima R. Cela O. D’Aprile A. Boffoli D. Falzetti F. Tabilio A. Capitanio N. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity.J. Biol. 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Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells.Stem Cells. 2008; 26: 960-968Crossref PubMed Scopus (505) Google Scholar), and hepatic stem cells (Turner et al., 2008Turner W.S. Seagle C. Galanko J.A. Favorov O. Prestwich G.D. Macdonald J.M. Reid L.M. Nuclear magnetic resonance metabolomic footprinting of human hepatic stem cells and hepatoblasts cultured in hyaluronan-matrix hydrogels.Stem Cells. 2008; 26: 1547-1555Crossref PubMed Scopus (44) Google Scholar). Stimulation of glycolysis in pluripotent stem cells, through hypoxia (Ezashi et al., 2005Ezashi T. Das P. Roberts R.M. Low O2 tensions and the prevention of differentiation of hES cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 4783-4788Crossref PubMed Scopus (682) Google Scholar; Mohyeldin et al., 2010Mohyeldin A. Garzón-Muvdi T. Quiñones-Hinojosa A. 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Bernard D. Gil J. Beach D. A high glycolytic flux supports the proliferative potential of murine embryonic stem cells.Antioxid. Redox Signal. 2007; 9: 293-299Crossref PubMed Scopus (259) Google Scholar). ESCs also have a high requirement for threonine metabolism to fuel anabolic pathways such as purine synthesis, with threonine withdrawal impairing cell growth and depleting stem cell markers (Wang et al., 2009Wang J. Alexander P. Wu L. Hammer R. Cleaver O. McKnight S.L. Dependence of mouse embryonic stem cells on threonine catabolism.Science. 2009; 325: 435-439Crossref PubMed Scopus (267) Google Scholar). Core pluripotency circuitry, including the OCT4, SOX2, and NANOG subset, shares points of convergence with STAT3, a master metabolic regulator controlling the oxidative to glycolytic switch (Chen et al., 2008cChen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. 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Cell Biol. 2009; 11: 320-327Crossref PubMed Scopus (80) Google Scholar). Chromatin modifiers, such as polycomb repressor complexes, which promote pluripotency, also target metabolic enzymes within their active gene sets (Brookes et al., 2012Brookes E. de Santiago I. Hebenstreit D. Morris K.J. Carroll T. Xie S.Q. Stock J.K. Heidemann M. Eick D. Nozaki N. et al.Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ESCs.Cell Stem Cell. 2012; 10: 157-170Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar; Dang, 2012Dang C.V. MYC on the path to cancer.Cell. 2012; 149: 22-35Abstract Full Text Full Text PDF PubMed Scopus (2106) Google Scholar). Moreover, kinase inhibitors (2i), which streamline germline-competent ESC derivation and prevent spontaneous differentiation, upregulate genes associated with metabolic functions (Marks et al., 2012Marks H. Kalkan T. Menafra R. Denissov S. Jones K. Hofemeister H. Nichols J. Kranz A. Stewart A.F. Smith A. Stunnenberg H.G. The transcriptional and epigenomic foundations of ground state pluripotency.Cell. 2012; 149: 590-604Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar). Key stemness transcriptional programs thus regulate energy metabolism to promote stem cell homeostasis. Development, envisioned in Waddington’s landscape, depicts gravity propelling a ball from a peak, representing pluripotency, to settle in local minimum elevation points of stable cell states (Enver et al., 2009Enver T. Pera M. Peterson C. Andrews P.W. Stem cell states, fates, and the rules of attraction.Cell Stem Cell. 2009; 4: 387-397Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). From the perspective of cell metabolism, the hills within the landscape represent thermodynamic barriers that segregate discrete cell states, with valleys corresponding to the minimum energetic paths connecting states, indicating that a specific metabolic capacity is required to overcome barriers to state conversion. Indeed, the energetic requirements of stem cells and their progeny differ; differentiated cells no longer need to sustain high rates of replication and thus have lower anabolic demands, but they require large amounts of energy to fuel the processes of cellular homeostasis and increasingly specialized functions of the progeny, such as sustained contraction in cardiomyocytes or electrical impulses in neurons (Folmes et al., 2012aFolmes C.D. Nelson T.J. Dzeja P.P. Terzic A. Energy metabolism plasticity enables stemness programs.Ann. N Y Acad. Sci. 2012; 1254: 82-89Crossref PubMed Scopus (73) Google Scholar). The lower requirement for anabolic precursors enables differentiated cells to catabolize substrates in a more energy efficient manner through complete oxidation within the TCA cycle, transfer of reducing equivalents to the electron transport chain, and production of ATP through oxidative phosphorylation, which for glucose produces 36 to 38 ATP compared to 2 ATP for glycolysis. Prioritization of discrete metabolic pathways offers a mechanism to align bioenergetic needs with evolving identities and specialized functions (Figure 3). Metabolomic comparison of ESCs and their differentiated progeny identified a global enrichment of unsaturated metabolites in the pluripotent state (Yanes et al., 2010Yanes O. Clark J. Wong D.M. Patti G.J. Sánchez-Ruiz A. Benton H.P. Trauger S.A. Desponts C. Ding S. Siuzdak G. Metabolic oxidation regulates embryonic stem cell differentiation.Nat. Chem. Biol. 2010; 6: 411-417Crossref PubMed Scopus (404) Google Scholar). Metabolites with a high degree of structural unsaturation contain a number of carbon-carbon double and triple bonds, which renders them reactive and readily susceptible to oxidative reactions. The unsaturated metabolome may prime ESCs to differentiate in response to oxidative processes, as levels of these metabolites decrease upon differentiation. In support of this concept, inhibition of the eicosanoid pathway in ESCs, which maintains high levels of unsaturated fatty acids, preserves pluripotency, while addition of saturated metabolites to ESC media supports oxidative metabolism and accelerates lineage specification (Yanes et al., 2010Yanes O. Clark J. Wong D.M. Patti G.J. Sánchez-Ruiz A. Benton H.P. Trauger S.A. Desponts C. Ding S. Siuzdak G. Metabolic oxidation regulates embryonic stem cell differentiation.Nat. Chem. Biol. 2010; 6: 411-417Crossref PubMed Scopus (404) Google Scholar). Consistent with an energetically privileged (primed) state, pluripotent cells display hyperpolarized mitochondria (Chung et al., 2007Chung S. Dzeja P.P. Faustino R.S. Perez-Terzic C. Behfar A. Terzic A. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells.Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: S60-S67Crossref PubMed Scopus (384) Google Scholar; Folmes et al., 2011aFolmes C.D. Nelson T.J. Martinez-Fernandez A. Arrell D.K. Lindor J.Z. Dzeja P.P. Ikeda Y. Perez-Terzic C. Terzic A. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming.Cell Metab. 2011; 14: 264-271Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar), poised to respond to an increase in energy demand during differentiation through efficient oxidative metabolism. Mitochondrial infrastructure and function can impact differentiation propensity independent of initial pluripotent features (Folmes et al., 2012bFolmes C.D.L. Dzeja P.P. Nelson T.J. Terzic A. Mitochondria in control of cell fate.Circ. Res. 2012; 110: 526-529Crossref PubMed Scopus (65) Google Scholar). ESCs with high resting mitochondrial membrane potential have more efficient teratoma formation and less efficient mesodermal differentiation compared to counterparts displaying low mitochondrial potential (Schieke et al., 2008Schieke S.M. Ma M. Cao L. McCoy Jr., J.P. Liu C. Hensel N.F. Barrett A.J. Boehm M. Finkel T. Mitochondrial metabolism modulates differentiation and teratoma formation capacity in mouse embryonic stem cells.J. Biol. Chem. 2008; 283: 28506-28512Crossref PubMed Scopus (156) Google Scholar). Redistribution of mitochondria from the perinuclear space throughout the cytosol during extended passaging of MSCs is associated with greater spontaneous differentiation (Lonergan et al., 2006Lonergan T. Brenner C. Bavister B. Differentiation-related changes in mitochondrial properties as indicators of stem cell competence.J. Cell. Physiol. 2006; 208: 149-153Crossref PubMed Scopus (140) Google Scholar). Slow-dividing mesoangioblasts, a precommitted cardiac progenitor cell, have extensive mitochondria and efficiently differentiate into cardiomyocytes, while their fast-dividing counterparts have few mitochondria that cannot support cardiac differentiation (San Martin et al., 2011San Martin N. Cervera A.M. Cordova C. Covarello D. McCreath K.J. Galvez B.G. Mitochondria determine the differentiation potential of cardiac mesoangioblasts.Stem Cells. 2011; 29: 1064-1074Crossref PubMed Scopus (35) Google Scholar). Stimulation of mitochondria biogenesis can overcome the differentiation block in fast-dividing cells, while reducing mitochondrial content perturbs cardiomyocyte differentiation in slow-dividing cells (San Martin et al., 2011San Martin N. Cervera A.M. Cordova C. Covarello D. McCreath K.J. Galvez B.G. Mitochondria determine the differentiation potential of cardiac mesoangioblasts.Stem Cells. 2011; 29: 1064-1074Crossref PubMed Scopus (35) Google Scholar). Mitochondrial and metabolic infrastructure thus prime stem cells for differentiation. When induced to differentiate, ESCs and MSCs downregulate stemness genes and stimulate mtDNA replication in support of mitochondrial biogenesis and maturation of extensive and interconnected networks of elongated and cristae-rich mitochondria (Chen et al., 2008bChen C.T. Shih Y.R. Kuo T.K. Lee O.K. Wei Y.H. 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