Stem cell lineage specification: you become what you eat

Abstract

Nutrient availability and intermediate metabolism are increasingly recognized to govern stem cell behavior. Oburoglu et al. (2014) now demonstrate that glutamine- and glucose-dependent nucleotide synthesis segregate erythroid versus myeloid differentiation during hematopoietic stem cell specification, implicating a metabolism-centric regulation of lineage choices.

Figure 1. Glutamine and glucose metabolism regulates hematopoietic stem cell lineage specification

Regulation of glutamine and glucose metabolism defines the ability of hematopoietic stem cells (HSC) to differentiate into erythroid versus myeloid lineages in vitro and in vivo. A) Glutamine uptake and glutaminolys is in support of de novo nucleotide biosynthesis and tricarboxylic acid cycle α-ketoglutarate generation are critical for HSC erythroid lineage commitment. Alternative metabolic pathways that support nucleotide synthesis, including 2-deoxyglucose (2-DG) blunting of glucose metabolism away from glycolys is toward the pentose phosphate pathway promotes erythropoiesis. B) In contrast, impairing nucleotide biosynthesis during erythropoietin-induced differentiation by impeding upstream glutamine synthesis (methionine sulfoximine, MSO), glutamine uptake, glutaminolys is (6-diao-5-oxo-L-norleucine, DON), transaminase reactions (aminooxyacetic acid, AOA) or blocking glucose entry into the pentose phosphate pathway (6-aminonicotinamide, 6-AN) skews lineage commitment away from erythroid, and toward myeloid fate. Supplementation with nucleosides rescues erythropoiesis, establishing the importance of de novo nucleotide biosynthesis for erythroid lineage commitment. GDH – glutamine dehydrogenase, GPAT – glutamine phosphoribosylpyrophosphateamidotransferase, GS – glutamine synthetase, G-6-P – glucose-6-phosphate, G6PD –glucose-6-phosphate dehydrogenase, PRA 5-Phosphoribosylamine, PRPP– 5-phosphoribosyl-1-pyrophosphate.