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.

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

“…Since only a small minority of these cells are HSCs, this strategy provides limited insight into metabolite levels in HSCs themselves. Others have characterized the phenotypes of mutant mice or metabolism in cultured hematopoietic stem and progenitor cells (Simsek et al, 2010, Ito et al, 2012, Ito et al, 2016, Ito et al, 2019, Wang et al, 2014, Ansó et al, 2017. However, it remains difficult to routinely compare metabolite levels between HSCs and other hematopoietic progenitors.…”

Fat for fuel: lipid metabolism in haematopoiesis

“…The regulation of haematopoiesis across the different stages of differentiation and commitment is crucial to modulating the balance of the mature blood cell compartments. Haematopoiesis is intrinsically regulated by stem and progenitor cell metabolism, with different metabolic parameters required for both proliferation (through symmetric mitosis) and differentiation (through asymmetric mitosis) across the various progenitors . Haematopoiesis is thus modulated by factors that influence cellular metabolism, including inflammatory signals and nutrient availability.…”

Ex vivo HSC expansion challenges the paradigm of unidirectional human hematopoiesis

“…Progressive increments in ROS levels, however, result in frequent cell divisions and HSC differentiation. 54,55 When ROS levels exceed the capacity of the cellular antioxidant defense, HSCs undergo senescence or cell death. 56 Thus, ROS act as rheostats that dictate HSC fate.…”