Stem Cell Energetics

Abstract

One of the most fascinating observations in the last few years in the field of hematopoietic stem cell (HSC) biology is that quiescence, the physiological state of dormancy that maintains the self-renewal of adult blood-forming HSCs, is governed primarily by metabolism. Hence, self-renewing HSCs rely mainly on anaerobic glycolysis for energy production, with a dash of fatty acid metabolism to support complex fate decisions like symmetric versus asymmetric divisions. At the same time, oxidative phosphorylation by the mitochondria has to be actively prevented to maintain cell quiescence. In contrast, HSC differentiation and active blood production requires the engagement of the TCA cycle to generate high levels of ATP, as well as increased production of reactive oxygen species (ROS) as a byproduct of mitochondrial activity, to help jump-start lineage commitment programs. While the hunt for the ultimate combination of surface markers that solely enrich for engrafting HSCs is still on, I have come to redefine HSCs based on their metabolic plasticity and ability to transition from dormancy to activity over a continuum of marker expression. Hence, in my view, the metabolic state and quiescent status, rather than the phenotypic identity, are the most important criteria for defining engrafting HSCs. This updated operational definition opens new perspectives for understanding HSC function in normal and disease contexts and for expanding engrafting HSCs in vitro for clinical applications. Dynamic PSC Mitochondria