Metabolic Regulation of Hematopoietic Stem Cells

Abstract

Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.

Metabolically Primed Multipotent Hematopoietic Progenitors Fuel Innate Immunity

“…To add a functional dimension to metabolic studies of rare cell types in vivo we developed MetaFate, a lineage tracing approach to perform state-fate mapping focused on metabolically-associated gene modules. Within a single mouse, there are an estimated 1.4 x 10 5 MPPs, representing just 0.03% of total bone marrow cellularity 2 . Consequently, cell yields falling far below the sensitivity limits of many metabolomics methods, making it technically challenging to study the metabolic properties of these rare subsets.…”

“…Recently developed population-level metabolomics, genetics, and pharmacological approaches show that cellular metabolism is a key regulator of hematopoietic stem cell (HSC) function 4,5 . At the top of the hematopoietic hierarchy, HSCs have been characterized by high rates of glycolysis 6 and low rates of protein preprint (which was not certified by peer review) is the author/funder.…”

“…Recently developed population-level metabolomics, genetics, and pharmacological approaches show that cellular metabolism is a key regulator of hematopoietic stem cell (HSC) function 4,5 . At the top of the hematopoietic hierarchy, HSCs have been characterized by high rates of glycolysis 6 and low rates of protein synthesis 7 , while glutamine 8 , mitophagy and fatty acid oxidation 9,10 , vitamin A 11 , ascorbate 12 and aspartate 13 have been shown to regulate HSC erythroid commitment, renewal, dormancy, abundance, and reconstitution capacity respectively.…”

“…At the top of the hematopoietic hierarchy, HSCs have been characterized by high rates of glycolysis 6 and low rates of protein synthesis 7 , while glutamine 8 , mitophagy and fatty acid oxidation 9,10 , vitamin A 11 , ascorbate 12 and aspartate 13 have been shown to regulate HSC erythroid commitment, renewal, dormancy, abundance, and reconstitution capacity respectively. As in many other stem cell systems, much work has focused on the metabolic regulation of stemness and quiescence, with relatively little focus given to the metabolic cues that guide downstream lineage specification 5,14,15 . Consequently, the metabolic processes needed to differentiate HSCs into immune cells are unknown.…”

Nuclear Myosin 1 regulates platelet activation and immune response in mice

“…The cell types present in bone marrow stroma include mesenchymal stem cells, fibroblasts, adipocytes, osteoblasts, osteoclasts and endothelial cells (Yu and Scadden, 2016). From the metabolic perspective, hematopoietic stem cells use anaerobic glycolysis as an only energy source and switch to oxidative phosphorylation only during differentiation (Morganti et al, 2022). Energy metabolism of fully differentiated hemopoietic cells depends on their function.…”