ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration

Abstract

In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5-fluorouracilinduced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCR high ) were enriched within the stem cell fraction at the expense of more proliferative EPCR Low HSCs. These EPCR High HSCs were initially more primitive than EPCR Low HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis-regulatory elements in progenitor cell-related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLYdependent histone acetylation promoted differentiation into CD48 + progenitor cells. Collectively, these results indicate that the dynamic control of ACLY-dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

“…Afterward, the NADH and FADH2 are used to fuel OXPHOS for ATP production [ 106 ]. Metabolic reprogrammed cells use the acetyl-CoA produced by FAO to energize the TCA cycle, generating additional TCA cycle intermediates, such as citrate, succinate, and aspartate [ 107 , 108 , 109 , 110 ].…”

Stem cells “aclymatise” to regenerate the blood system

“…In the late phase after 5‐FU administration, HSCs acquire differentiation potential through increased accessibility of progenitor cell‐related cis ‐regulatory regions, while histone acetylation suppression due to decreased mitochondria‐Acly activity allows for HSC maintenance by repressing genes with increased accessibility. Figure based on fig EV5C of Umemoto et al (2022).…”

“…This “fine‐tuning” is the result of a complex interplay between HSC‐intrinsic mechanisms and signals from the specialised bone marrow microenvironment, which regulates HSC quiescence during haematopoietic regeneration (Silberstein et al , 2016; Fielding et al , 2022). In this issue, an elegant study by Umemoto et al (2022) investigates the contribution of HSC subsets to haematopoietic recovery and identifies unexpected links between metabolic and epigenetic HSC regulation dependent on acetyl‐CoA and its biosynthetic enzyme, Acly.…”

“…In their study, Umemoto et al (2022) analyse two different stages of haematopoietic recovery after 5‐fluorouracil (5‐FU), a drug commonly used to treat cancer, since it eliminates proliferative cells. In the haematopoietic system, 5‐FU reduces proliferative HSCs expressing low levels of endothelial protein receptor (EPCR low ), while it spares quiescent EPCR high HSCs, which subsequently play a key role during the early phase of haematopoietic regeneration (3–7 days after 5‐FU).…”

“…Interrogating potential mechanisms responsible for the dynamic changes observed in chromatin during haematopoietic regeneration, Umemoto et al (2022) focus on acetyl‐CoA, which is a major regulator of histone acetylation, and its biosynthetic enzyme, Acly. They find that Acly mRNA, protein and phosphorylation (p‐Ser455) levels in HSCs exhibit similar dynamics as H3K27ac—increasing during the early phase of haematopoietic recovery, to decrease later.…”