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.

脂肪酸β-氧化（FAO）是脂质的分解，是各种干细胞使用的代谢途径。静止期粮农组织的水平通常很高，并且随着增殖而下调。内源性代谢物丙二酰辅酶A调节脂质代谢，作为可逆的FAO抑制剂和从头脂肪形成的底物。在这里，我们评估了丙二酰辅酶A是否可以用于指导造血干/祖细胞（HSPCs），具有临床意义的静态干细胞的行为。与未经处理的对照组相比，丙二酰辅酶A体外处理小鼠HSPC可以增加HSPC数量，并改善体内移植时的血液重建能力，主要是通过增强淋巴重构。类似地，在体外丙二酰辅酶A处理后，人类HSPC数量也增加。这些数据证实脂质代谢可以靶向直接的细胞命运和干细胞增殖。代谢途径的生理调节，而不是遗传或药理学抑制作用，为健康和疾病中干细胞的操作提供了独特的见解。