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Epigenetic Metabolites License Stem Cell States CHAPTER SIX Epigenetic metabolites license stem cell states Logeshwaran Somasundarama,b,†, Shiri Levya,b,†, Abdiasis M. Husseina,b, Devon D. Ehnesa,b, Julie Mathieub,c, Hannele Ruohola-Bakera,b,∗ aDepartment of Biochemistry, University of Washington, Seattle, WA, United States bInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States cDepartment of Comparative Medicine, University of Washington, Seattle, WA, United States ∗ Corresponding author: e-mail address: [email protected] Contents 1. Introduction 210 2. Stem cell energetics 210 3. Metabolism of quiescent stem cells 212 3.1 Adult stem cells 212 3.2 Pluripotent stem cell quiescence, diapause 216 4. Metabolism of active stem cells 217 4.1 Metabolism after fertilization 217 4.2 Metabolism of pre-implantation and post-implantation pluripotent stem cells 218 4.3 Metabolism of actively cycling adult stem cells: MSC as case-study 220 5. HIF, the master regulator of metabolism 222 6. Epigenetic signatures and epigenetic metabolites 224 6.1 Epigenetic signatures of naïve and primed pluripotent stem cells 224 6.2 Epigenetic signatures of adult stem cells 227 6.3 Epigenetic metabolites 228 7. Conclusion 229 Acknowledgments 230 References 230 Further reading 240 Abstract It has become clear during recent years that stem cells undergo metabolic remodeling during their activation process. While these metabolic switches take place in pluripotency as well as adult stem cell populations, the rules that govern the switch are not clear. † Equal contribution. # Current Topics in Developmental Biology, Volume 138 2020 Elsevier Inc. 209 ISSN 0070-2153 All rights reserved. https://doi.org/10.1016/bs.ctdb.2020.02.003 210 Logeshwaran Somasundaram et al. In this review, we summarize some of the transitions in adult and pluripotent cell types and will propose that the key function in this process is the generation of epigenetic metabolites that govern critical epigenetic modifications, and therefore stem cell states. 1. Introduction Stem cells have dynamic metabolic programs that support their constant capacity to regenerate. These metabolic signatures are proposed to propagate cell fate changes (Bracha, Ramanathan, Huang, Ingber, & Schreiber, 2010; Folmes et al., 2011; Greer, Metcalf, Wang, & Ohh, 2012; Panopoulos et al., 2011; Rafalski, Mancini, & Brunet, 2012; Yanes et al., 2010), which alter as the cells become increasingly specified. Recent studies are revealing that these metabolic shifts go beyond direct metabolic needs for energy production and expand into the production of specific metabolites that have epigenetic implications for cell fate (Buck et al., 2016; Gasco´n et al., 2015; Mathieu & Ruohola-Baker, 2017; Zhang, Mei, et al., 2016; Zhang, Ryu, et al., 2016; Zhang, Termanis, et al., 2016; Zheng et al., 2016). This review aims to understand the potential rules for this interdependence. Many adult stem cells stay in a quiescent state, until the signals from the environment demand their contribution to regenerate the tissue. As it turns out, the early embryo can also stop the developmental trajectory temporarily in a quiescent state. This mechanism, known as diapause, is used by over a hundred mammals including roe deer, kangaroos and koala bears in order to temporarily halt their pregnancy when conditions make it unlikely that the progeny will survive. We will compare and contrast the metabolic differ- ences in quiescent and activated adult and pluripotent stem cells, and their epigenetic patterns. 2. Stem cell energetics Cellular metabolism is the set of all biochemical reactions that produce the energy, and irrespective of cell type or differentiation state, it is required to support the intricate molecular machinery that keeps the cell alive. Metabolic processes can be broken down into either synthesis of new bio- molecules (anabolism) or breaking down of molecules and existing biomol- ecules (catabolism) to generate energy. Several pathways are involved in the building up and breaking down of biomolecules and cellular components. Epigenetic metabolites license stem cell states 211 In this review, we consider glycolysis, pentose phosphate pathway, tricarboxylic acid (TCA) cycle, fatty acid β-oxidation and oxidative phos- phorylation (Fig. 1). Glycolysis is a metabolic pathway that converts glucose into pyruvate while generating ATP and NADPH. Biosynthetic intermedi- ates from glycolysis can be directed into the pentose phosphate pathway (PPP) for cell growth and proliferation. PPP is shown to be an essential metabolic pathway for pluripotent stem cells (Filosa et al., 2003; Varum et al., 2011) because it generates metabolites that are needed for lipid and nucleotide biosynthesis. Some adult stem cells also require this pathway since the PPP enzyme hexose-6-phosphate dehydrogenase (H6PD) was found to be required for the self-renewal of myoblast in vitro during muscle Glucose Pentose phosphate pathway G6P Nucleotide biosynthesis Lipid synthesis F6P G3P Glycolysis ADP ATP Lactate Pyruvate Fatty acid β-oxidation Pyruvate Mitochondrion Acetyl-CoA Oxaloacetate Citrate + OXPHOS FADH2 TCA NAD FAD cycle NADH ETC Succinate Succinyl CoA ADP ATP synthase ATP Cytoplasm Fig. 1 Overview of the major cellular metabolic pathways (indicated in blue): Glycolysis, pentose phosphate pathway (PPP), TCA (Krebs) cycle, β-oxidation and oxidative phosphorylation (OXPHOS). Metabolites from glycolysis can move to PPP to generate NADPH and precursors for lipid and nucleotide synthesis. In addition to generating ATP, glycolysis generates pyruvate which is oxidized in the TCA cycle. OXPHOS gener- ates the most ATP in the electron transport chain (ETC). Adult and pluripotent stem cells both utilize these metabolic pathways (see text for details). ADP, adenosine diphos- phate; ATP, adenosine triphosphate; ATPase, ATP synthase; ETC, electron transport chain; F6P, fructose 6 phosphate; G6P, glucose 6 phosphate; G3P, glyceraldehyde- 3-phosphate; FAD, Flavin adenine dinucleotide; NAD, Nicotinamide adenine dinucleo- tide; TCA, tricarboxylic acid. The figure was created with Biorender.com. 212 Logeshwaran Somasundaram et al. regeneration (Bracha et al., 2010). In the presence of oxygen, pyruvate gen- erated from glycolysis can be transported into mitochondria and converted into acetyl-CoA. However, in low oxygen conditions (hypoxia) pyruvate will be reduced to lactate and a free energy carrier, NAD+ is generated. In addition to glucose, lipids are a major source of energy in cells. Energy is generated from lipid breakdown through fatty acid β-oxidation, producing acetyl-CoA. Long chain fatty acids are transported to mitochon- dria by the carnitine acyl transferase, CAT, system, also known as the carnitine shuttle. The rate limiting enzyme in this step is CAT1. Fatty Acyl-CoA is then dehydrogenated to acetyl-CoA utilizing the mito- chondrial trifunctional protein (TFP) consisting of enoyl-CoA hydratase, hydroxyacyl-CoA dehydrogenase A and B (HADHA and HADHB) and ketoacyl-CoA thiolase. Defects in components of this pathway are causa- tive for LCHAD deficiency, resulting in sudden infant death syndrome (SIDS) in humans (Miklas et al., 2019). Each cycle in the TFP complex results in a fatty acyl-CoA moiety that is shorter by two carbons and an acetyl-CoA that can enter the TCA cycle. Acetyl-CoA produced either from glucose or from fatty acid β-oxidation is oxidized in the TCA cycle in a series of reactions that ultimately generate ATP and CO2. TCA cycle generates important metabolic intermediates and electron carriers, FADH2 and NADH. Electrons carried by NADH and FADH2 into the electron transport chain will generate a proton gradient across the inner mitochondrial membrane. The energy from this proton gradient is finally captured in the form of ATP by the conversion of ADP and phosphate to ATP by ATP-β-synthase, a rotating molecular machine that taps its energy from utilizing the chemiosmotic proton [H+] gradient to power its movement. The rotating movement is critical for catalytic site to access ADP and phosphate to generate ATP. The synthesis of ATP by ATP-β synthase is a process known as oxidative phosphorylation (OXPHOS) (Fig. 1). 3. Metabolism of quiescent stem cells 3.1 Adult stem cells In general, most tissues have resident stem cell populations, most of which exist in a relatively quiescent state and serve to repopulate old or injured cells within that organ. Some examples of these adult stem cell types can be iden- tified in brain, teeth, gut, bone marrow (HSC and MSC), skin, hair follicle, testicles, and skeletal muscle (satellite cells). Here, we will discuss three of Epigenetic metabolites license stem cell states 213 these adult stem cell types: satellite cells, hematopoietic stem cells (HSC) and hair follicle stem cells. These types of stem cells reside in a quiescent stage until they receive an activating signal for regeneration. The quiescent stage may have cellular advantages, protecting the cell from damage, allowing repair, or allowing an existence of specific metabolic state (Fig. 2). 3.1.1 Satellite cell metabolic switch during activation Satellite cells are small, mononucleated cells found on a surface of skeletal muscles that can partake in the regeneration of injured muscle by self- renewing, undergoing myogenic differentiation and finally fusing to a dam- aged muscle fiber to induce repair. These muscle stem cells remain quiescent during healthy resting periods (Cheung & Rando, 2013) by commu- nications and factors by surrounding environment (Baghdadi
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