The metabolic programming of stem cells

Abstract

Advances in metabolomics have deepened our understanding of the roles that specific modes of metabolism play in programming stem cell fates. Here, we review recent metabolomic studies of stem cell metabolism that have revealed how metabolic pathways can convey changes in the extrinsic environment or their niche to program stem cell fates. The metabolic programming of stem cells represents a fine balance between the intrinsic needs of a cellular state and the constraints imposed by extrinsic conditions. A more complete understanding of these needs and constraints will afford us greater mastery over our control of stem cell fates.

Keywords: metabolomics; oxidative phosphorylation; stem cell.

Figure 1.

The metabolic programming of naïve and primed pluripotency states in mouse PSCs, for which the culture conditions are well established and the metabolic reactions are well characterized. Mitochondrial reactions that are more enriched in naïve (than primed) PSCs are marked in green, while cytosolic reactions that are more enriched in primed (than differentiated) PSCs are marked in red. Pyruvate essentially has three fates: (1) cytosolic reduction to lactate, (2) cytosolic conversion to acetyl-CoA via citrate, and (3) mitochondrial oxidation via the Krebs cycle. These metabolic pathways are not exclusive to PSCs but are highly prominent in PSCs to regulate histone acetylation and methylation in the chromatin, thereby influencing the epigenomic state and cell fate of PSCs.

Figure 2.

The metabolic programming of quiescent and proliferating adult stem cells relative to oxygen availability. A common theme is that quiescent adult stem cells in hypoxic niches tend to prefer glycolysis and fatty acid oxidation with high levels of nuclear NRF2- or FoxO-driven (blue) antioxidant enzyme expression to suppress ROS signaling. In contrast, proliferative adult stem cells tend to use more oxygen in a normoxic environment under the influence of growth factor kinase signaling, lower their expression of antioxidant enzymes, and activate ROS signaling (yellow). The resultant burst in proliferation also leads to irreversible commitment as the adult stem cells proliferate and differentiate into tissue-specific progeny. This model is based largely on studies in HSCs, but emerging evidence suggests that it could apply generally to many other adult stem cells.

Figure 3.

Unified summary of common metabolic features often observed during both PSC and adult stem cell differentiation. During self-renewal, both PSCs and adult stem cells maintain their multipotent capacity and a relatively open chromatin state. In conjunction with their epigenomic status, glycolysis and mitochondrial (glutamine or fatty acid) oxidation tend to be used, but total OxPhos flux and ROS levels typically stay low in a hypoxic environment. Proliferation of committed progenitors typically coincides with high glycolysis and a burst of ROS in a normoxic environment (see Fig. 2), while mitochondrial oxidation begins to rise. Further differentiation often leads to a decline in glycolysis and a further increase in mitochondrial oxidation.