Energy Metabolism Regulates Stem Cell Pluripotency

Abstract

Pluripotent stem cells (PSCs) are characterized by their unique capacity for both unlimited self-renewal and their potential to differentiate to all cell lineages contained within the three primary germ layers. While once considered a distinct cellular state, it is becoming clear that pluripotency is in fact a continuum of cellular states, all capable of self-renewal and differentiation, yet with distinct metabolic, mitochondrial and epigenetic features dependent on gestational stage. In this review we focus on two of the most clearly defined states: "naïve" and "primed" PSCs. Like other rapidly dividing cells, PSCs have a high demand for anabolic precursors necessary to replicate their genome, cytoplasm and organelles, while concurrently consuming energy in the form of ATP. This requirement for both anabolic and catabolic processes sufficient to supply a highly adapted cell cycle in the context of reduced oxygen availability, distinguishes PSCs from their differentiated progeny. During early embryogenesis PSCs adapt their substrate preference to match the bioenergetic requirements of each specific developmental stage. This is reflected in different mitochondrial morphologies, membrane potentials, electron transport chain (ETC) compositions, and utilization of glycolysis. Additionally, metabolites produced in PSCs can directly influence epigenetic and transcriptional programs, which in turn can affect self-renewal characteristics. Thus, our understanding of the role of metabolism in PSC fate has expanded from anabolism and catabolism to include governance of the pluripotent epigenetic landscape. Understanding the roles of metabolism and the factors influencing metabolic pathways in naïve and primed pluripotent states provide a platform for understanding the drivers of cell fate during development. This review highlights the roles of the major metabolic pathways in the acquisition and maintenance of the different states of pluripotency.

Keywords: amino acids; glycolysis; induced pluripotent stem cells; naïve and primed embryonic stem cells; nuclear reprogramming; oxidative metabolism; oxidative phosphorylation; tricarboxylic acid cycle.

FIGURE 1

Transitions between human pluripotent stem cell (PSC) states. Human embryonic stem cells derived from the inner cell mass of the blastocyst or through nuclear reprogramming traditionally display a primed state associated with bivalent metabolism using both glycolysis and oxidative phosphorylation (OxPhos). Methods have now been developed to derive naïve PSCs (t2iLGö ± Y, RSeT) or to transition cells from the primed to naïve state (5i/L/AF, or Klf4, Nanog, 2i/L), resulting in a transition from bivalent metabolism to nearly exclusively glycolysis. These metabolic preferences reflect those of the related stage during embryonic development.

FIGURE 2

Overview of the major metabolic pathways in pluripotent stem cells and their regulators. Major metabolic pathways are found in blue boxes and key sites of regulation are highlighted in blue rectangles. Identified upstream regulators of metabolic pathways are depicted as orange rectangles and the directionality of regulation represented by red bars (suppression) or green arrows (activation).

FIGURE 3

Metabolic preferences of naïve and primed pluripotent stem cells (PSCs). Major metabolic pathways identified in PSCs are listed on the left and arrows depicting directionality (yellow = elevated, blue = suppressed) and magnitude (thickness) of differences relative to somatic cells.

FIGURE 4

Metabolic remodeling drives nuclear reprogramming. Summary of the temporal changes in upstream regulators, the downstream metabolic changes and the consequences of this metabolic phenotype on nuclear reprogramming.