Fatty Acid Synthase Restrains Self-Renewal in Hematopoietic Stem Cells

Abstract

Hematopoietic stem cells (HSCs) are a rare pool of somatic stem cells essential for blood production and organismal survival. Despite their importance, little is known about the metabolic regulation of HSCs during steady-state and stressed conditions. There is evidence to suggest that fatty acid metabolism plays a key role in HSC function. However, the importance of de novo lipogenesis (DNL) in HSCs is still not understood. DNL proceeds through two major steps, catalyzed by the enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN). Here, we investigate the roles of these two critical enzymes in the context of HSC function and maintenance. With conditional gene knockout mouse models, we determined that ACC1, but not FASN, is essential for steady-state hematopoiesis. When examining stem cell fitness through competitive bone marrow transplantation assays, we observed that the loss of FASN produces a competitive advantage in HSCs, with stem cells exhibiting enhanced self-renewal potential over multiple rounds of serial transplantation. Our research suggests that FASN restrains self-renewal in HSCs through an unknown mechanism, and that DNL plays an uncharacterized but significant role in HSC function.