Surviving change: the metabolic journey of hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that maintain blood production and are uniquely wired to adapt to diverse cellular fates during the lifetime of an organism. Recent studies have highlighted a central role for metabolic plasticity in facilitating cell fate transitions and in preserving HSC functionality and survival. This review summarizes our current understanding of the metabolic programs associated with HSC quiescence, self-renewal, and lineage commitment, and highlights the mechanistic underpinnings of these changing bioenergetics programs. It also discusses the therapeutic potential of targeting metabolic drivers in the context of blood malignancies.

Keywords: blood; fatty acid oxidation; glycolysis; hematopoietic stem cells; quiescence; reactive oxygen species.

Figure 1

Metabolic drivers as determinants of HSC cell fate. The ‘ground state’ of adult HSCs is a ROS-low and ATP-low quiescent state, which is enforced by anaerobic glycolysis. Activation of energy generating metabolic pathways such as the TCA cycle and FAO pathway produce high ATP and ROS levels, which drive an ‘active state’ where HSCs are pushed towards commitment and differentiation through asymmetric cell divisions. Blockade of energy generating metabolic programs triggers symmetric cell divisions, which either expand HSCs or their progeny. A shifting balance between these different metabolic programs likely contributes to HSC function in normal, regenerative and disease conditions.

Figure 2

Cross-antagonistic and self-re-enforcing metabolic signaling in HSCs. Upon activation by receptor tyrosine kinases (RTKs), the PI3K-mTOR axis drive HSC proliferation and differentiation by increasing ROS production and repressing the FAO signaling module. In contrast, low energy levels activate the LKB1/AMKP pathway that promote HSC quiescence and self-renewal via FAO modulation and inhibition of the ROS signaling module.

Figure 3

Targeting the metabolic machinery in LSCs. LSCs are major drivers of leukemia initiation and maintenance and underlie drug resistance. Therapeutic strategies aimed at inducing cell cycle entry, disrupting energy generation, attenuating oxidative damage and promoting differentiation have been proposed as ways to selectively target or kill LSCs while sparing normal HSCs.