Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate

Abstract

Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases.

Fig. 1.

Energy sources in stem and differentiated cells. Many stem cell niches exhibit low oxygen concentrations. Stem cells appear to generate ATP mainly through glycolysis, which is independent of oxygen. Under low oxygen (<9% O₂), the hypoxia-inducible factor 1α (HIF1α) is stabilized and binds to its partner HIF1β. The HIF1 heterodimer binds to hypoxia response elements to control the expression of genes involved in glucose metabolism and transport, the cell cycle and cell death. HIF1 activity appears to have an active role in the regulation of stem cell metabolism, as it can induce stem cells to shift towards a predominantly anaerobic glycolytic metabolism. Conversely, differentiated cells generate ATP largely through oxidative phosphorylation, which requires oxygen. ETC, electron transport chain; TCA, tricarboxylic acid.

Fig. 2.

Nutrient-sensing pathways in stem cells. Nutrient and energy-responsive signaling pathways impact stem cells in a variety of ways. Shown here is a schematic illustration of the cellular components that respond to energy availability to influence stem cell metabolism and fate. Blue shading highlights molecules that are active in a high-energy state. Red shading highlights molecules that are inactive in a high-energy state, or that are active in response to cellular stresses, such as low oxygen and low energy. AKT, protein kinase B; AMPK, AMP-activated protein kinase; ETC, electron transport chain; FOXO, Forkhead Box O; HIF1, hypoxia-inducible factor 1; Insulin–IGF1R:insulin–insulin-like growth factor 1 receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; SIRT1, Sirtuin 1; SGK1, serum-glucocorticoid regulated kinase 1; S6K1, ribosomal S6 protein kinase 1; TCA, tricarboxylic acid cycle (also known as Krebs cycle or citric acid cycle); 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1.

Fig. 3.

The impact of organismal metabolism on stem cell fate. Schematic diagram of how energy availability and metabolic state of a whole organism can influence stem cells, either directly or indirectly. Nutrient availability can be influenced by food consumption, metabolic disorders, or, in the case of the fetus, maternal diet. Obesity and dietary restriction are two examples of extremes of nutrient availability, the former is closely associated with type II diabetes, a widespread disease of insulin resistance, whereas the latter is associated with health benefits in many species (Fontana et al., 2010). Studies examining how diabetes and other diseases of metabolism alter stem cell function are beginning to emerge. For example, mobilization of HSCs by granulocyte colony-stimulating factor (G-CSF) is impaired in both diabetic human patients and mouse models of type I or type II diabetes (Ferraro et al., 2011). In the brains of rodents with either type I or type II diabetes, NSC proliferation and neurogenesis are reduced in the hippocampus in a corticosterone-dependent manner (Rafalski and Brunet, 2011; Stranahan et al., 2008). Conversely, dietary restriction (30% reduction in calorie intake without malnutrition) enhances the survival of newborn neurons in the adult rodent hippocampus (Lee et al., 2000). These studies highlight how stem cells can respond dramatically to organismal changes in metabolic homeostasis and argue that more studies need to be conducted to characterize not only how stem cell populations are affected by disordered metabolism, but also how pharmaceutical drugs that are used to treat these metabolic conditions affect stem cells. Maternal nutrition also has the potential to impact the fetus through changes in stem cell fate. The Dutch famine during World War II is an example of how starvation in pregnant mothers can result in glucose intolerance, cognitive dysfunctions, and greater risk for breast cancer and heart disease in offspring that were developing embryos during the time of maternal starvation (de Rooij et al., 2010; Roseboom et al., 2006). Although the effects of maternal starvation on stem cells of the fetus are not known, in utero changes in metabolism are likely to have a key function in the regulation of stem cells and the tissues that develop from them.