Editors' ChoiceStem Cells

A Curious Case of Cellular Metabolism

Science Translational Medicine  06 Jul 2011:
Vol. 3, Issue 90, pp. 90ec103
DOI: 10.1126/scitranslmed.3002829

Abstract

In the F. Scott Fitzgerald short story The Curious Case of Benjamin Button, a man is born elderly and ages in reverse. Similarly, human induced pluripotent stem cells (iPSs) begin life as fully differentiated agents and are reprogrammed to resemble the human embryonic stem cell (hESC) state. But how closely the biology of iPSs mimic that of hESCs is an area of intense research. We can speculate lightly about whether Ben’s cells grew metabolically younger with time, but characterization of the metabolic signatures of iPSs and hESCs is crucial if these cells are to be exploited in the therapeutic arena. Now, Varum and colleagues compare energy metabolism in hESCs as well as in iPSs and their differentiated somatic counterparts.

hESCs mostly depend on glycolysis for energy generation. As these cells differentiate, their mitochondria mature and energy production shifts from (cytoplasmic) glycolysis to oxidative phosphorylation via the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain. Varum et al. demonstrated that mitochondria in hESCs are indeed immature, with fewer cristae—internal membranous compartments that house the energy-generating machinery—and a lower electron density matrix (and thus lower levels of energy production) as compared with differentiated somatic cells. In contrast, iPSs displayed mitochondrial features of both hESCs and somatic cells. iPSs differed from hESCs with respect to glucose metabolism–related gene expression, although in a heat map these two cell types clustered together rather than with their somatic counterparts. Furthermore, despite elevated expression of genes that encode TCA cycle enzymes and an increase in components of the electron transport chain, both human iPS and hESC mitochondria were hypofunctional compared to somatic cells as shown by lower oxygen consumption rates, reduced ATP production, and increased lactate production. Finally, this study demonstrated a significantly higher expression of hexokinase II and inactivation of the pyruvate dehydrogenase (PDH) complex in iPSs relative to somatic cells. Hexokinase II catalyzes the first and rate-limiting reaction of glycolysis by converting glucose to glucose 6-phosphate. The PDH complex is localized in the mitochondrial matrix and irreversibly decarboxylates pyruvate (a product of glycolysis) to acetyl coenzyme-A in a reaction that links glycolysis to the TCA cycle.

Taken together, these results indicate that human iPSs like hESCs and in contrast to somatic cells, rely more on glycolysis than on oxidative phosphorylation for energy production. Many types of tumor cells and perhaps cancer stem cells share similar metabolic signatures with hESCs and iPSs. Thus, it is of great interest to determine whether and how iPSs acquire a more glycolytic-based metabolic scheme upon reprogramming with the goal of using iPSs to design therapeutic strategies that selectively target metabolic pathways in cancer cells.

S. Varum et al., Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS ONE 6, e20914 (2011). [Full Text]