Metabolism as master of hematopoietic stem cell fate

Abstract

HSCs have a fate choice when they divide; they can self-renew, producing new HSCs, or produce daughter cells that will mature to become committed cells. Technical challenges, however, have long obscured the mechanics of these choices. Advances in flow-sorting have made possible the purification of HSC populations, but available HSC-enriched fractions still include substantial heterogeneity, and single HSCs have proven extremely difficult to track and observe. Advances in single-cell approaches, however, have led to the identification of a highly purified population of hematopoietic stem cells (HSCs) that make a critical contribution to hematopoietic homeostasis through a preference for self-renewing division. Metabolic cues are key regulators of this cell fate choice, and the importance of controlling the population and quality of mitochondria has recently been highlighted to maintain the equilibrium of HSC populations. Leukemic cells also demand tightly regulated metabolism, and shifting the division balance of leukemic cells toward commitment has been considered as a promising therapeutic strategy. A deeper understanding of precisely how specific modes of metabolism control HSC fate is, therefore, of great biological interest, and more importantly will be critical to the development of new therapeutic strategies that target HSC division balance for the treatment of hematological disease.

Keywords: Cellular metabolism; Hematopoietic stem cell; Leukemia; Mitochondria; Stem cell fate.

Fig. 1

Key metabolic pathways in hematopoietic stem cells. a Representative deconvoluted immuno-fluorescent images of mitochondria (top) and mitochondrial functions (bottom). Mitochondria are important bioenergetic and biosynthetic organelles, and are also involved in cell signaling pathways. The reducing equivalents generated by the tricarboxylic acid (TCA) cycle are fed to the electron transport chain (ETC) to drive the synthesis of ATP molecules. b Hematopoietic stem cells (HSCs) rely on glycolysis, which is promoted by hypoxiainducible factor 1α (HIF-1α). Valine, one of the essential amino acids (EAAs), is required for the proliferation and maintenance of HSCs. The intermediate of the TCA cycle, α-ketoglutarate (αKG), is a cofactor for dioxygenase enzymes

Fig. 2

Quality control of mitochondria promotes HSC self-renewal. a The mechanisms of mitophagy, a selective removal process of mitochondria, has been extensively explored, and one of the best-understood pathways in this process is Pink1/Parkin-mediated mitophagy. In healthy mitochondria, Pink1 is imported and constitutively degraded. In depolarized mitochondria, Pink1 (red) is stabilized on the outer mitochondrial membrane and facilitates the recruitment of cytosolic Parkin (green). Activation of Parkin leads to the ubiquitination (orange) of multiple outer protein substrates, which are recognized by specific mitophagy receptors. Phagophore (pale green) surrounds the damaged mitochondrion, which is subsequently delivered to the lysosomal clearance. b Upon cell division, organelles such as mitochondria may be damaged, which promotes mitochondrial quality control, which in turn supports the self-renewal of HSCs. Failure to clear the damaged mitochondria could lead to HSC exhaustion