A Single Metabolite which Modulates Lipid Metabolism Alters Hematopoietic Stem/Progenitor Cell Behavior and Promotes Lymphoid Reconstitution

Abstract

Summary Fatty acid β-oxidation (FAO), the breakdown of lipids, is a metabolic pathway used by various stem cells. FAO levels are generally high during quiescence and downregulated with proliferation. The endogenous metabolite malonyl-CoA modulates lipid metabolism as a reversible FAO inhibitor and as a substrate for de novo lipogenesis. Here we assessed whether malonyl-CoA can be exploited to steer the behavior of hematopoietic stem/progenitor cells (HSPCs), quiescent stem cells of clinical relevance. Treatment of mouse HSPCs in vitro with malonyl-CoA increases HSPC numbers compared with nontreated controls and ameliorates blood reconstitution capacity when transplanted in vivo , mainly through enhanced lymphoid reconstitution. Similarly, human HSPC numbers also increase upon malonyl-CoA treatment in vitro . These data corroborate that lipid metabolism can be targeted to direct cell fate and stem cell proliferation. Physiological modulation of metabolic pathways, rather than genetic or pharmacological inhibition, provides unique perspectives for stem cell manipulations in health and disease.

Lipid metabolism in focus: how the build-up and breakdown of lipids affects stem cells

“…In line with this concept, we have recently shown that malonyl-CoA affects HSCs (Giger et al, 2020). Malonyl-CoA is the endogenous inhibitor of CPT1A and at the same time, a key substrate for FASN (Box 1).…”

“…The addition of this single metabolite to a classical HSC culture medium is sufficient to increase mouse and human HSC numbers in vitro. Furthermore, mouse HSCs grown in this condition have an enhanced lymphoid repopulation capacity upon transplantation in vivo (Giger et al, 2020). With aging, HSCs display a myeloid bias and fewer lymphoid cells are produced, which can lead to reduced immune functions (Kovtonyuk et al, 2016).…”

“…With aging, HSCs display a myeloid bias and fewer lymphoid cells are produced, which can lead to reduced immune functions (Kovtonyuk et al, 2016). Addition of malonyl-CoA even partially reverts the myeloid bias in aged mouse HSCs in vitro, suggesting that modulation of lipid metabolism in HSCs can also affect fate (Giger et al, 2020). As malonyl-CoA has a dual function on DNL and FAO, it is difficult to say which of the two pathways is responsible for the observed effects without further experiments.…”

Myelodysplastic Syndromes and Metabolism

“…The breakdown of lipids, termed fatty acid β-oxidation (FAO), is increased in myeloid malignancies associated with enhanced autophagy, which, in turn, also supports OXPHOS specifically in malignant cells but not in normal cells; this leads to proliferation and growth of malignant clones [ 42 ]. Thus, pharmacological modulation of FAO, e.g., with the reversible FAO inhibitor malonyl-CoA, is considered a potential therapeutic intervention to modulate malignant cell fate and, possibly, to influence normal hematopoiesis [ 43 ].…”

Myeloid Metabolism as a New Target for Rejuvenation?-Comments on Restoring Metabolism of Myeloid Cells Reverses Cognitive Decline in Ageing. Nature. 2021 Feb;590(7844)122-128

“…Cellular metabolism has emerged as a key player in the regulation of immune function [ 7 – 9 ], starting already at the level of myeloid versus lymphoid lineage decision [ 10 , 11 ] and greatly affecting cellular behaviour in the mature immune cells. Several recent studies have suggested that an altered cellular metabolism in aged macrophages might directly contribute to the pro-inflammatory signature [ 12 – 14 ].…”