Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells

Abstract

Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis. At the molecular level, Cited2 deficiency significantly reduced the expression of genes involved in metabolism, such as Pdk2, Pdk4, and lactate dehydrogenases B and D (LDHB and LDHD). Cited2-deficient HSCs also exhibited increased Akt signaling, concomitant with elevated mTORC1 activity and phosphorylation of FoxOs. Further, inhibition of PI3/Akt, but not mTORC1, partially rescued the repression of Pdk4 caused by deletion of Cited2. Altogether, our results suggest that Cited2 is required for the maintenance of adult HSC glycolytic metabolism likely through regulating Pdk2, Pdk4, LDHB, LDHD, and Akt activity.

HIF-1α inhibition by 2-methoxyestradiol induces cell death via activation of the mitochondrial apoptotic pathway in acute myeloid leukemia

“…In addition, our results showed that 2ME2 downregulated CITED2 mRNA expression, which plays a critical role in HSC metabolic regulation. 25 Suppression of CITED2 may increase apoptosis and impaire leukemia stem cell function. However, the details of the mechanism remain to be elucidated.…”

“…CITED2, a hypoxia-and growth factorinduced transcription factor, is a negative regulatory factor to HIF-1a that acts to disrupt the interaction between HIF-1a and p300. 15 However, it has been reported that CITED2 expression has a functional role in AML maintence, 24 attenuation glycolytic metabolism, and elevation of mitochondrial activity, 25 similar to HIF-1a. Although CITED2 and HIF-1 are competitive in the regulation of hypoxia, they have similar functions in the maintenance of HSCs.…”

Metabolic requirements for the maintenance of self-renewing stem cells

“…For example, MEIS1 regulates both glycolysis and the oxidative stress response by activation of Hif1a transcription in HSCs 30 . Moreover, the homeobox protein CBP/p300-interacting transactivator 2 (CITED2) was found to be essential for the maintenance of HSC quiescence, in part by transcriptionally activating Hif1a , thereby increasing HIF activity 49–51 .…”

Stem cells and the impact of ROS signaling

“…Similar to ESCs, HSCs also contain relatively immature mitochondria, suggesting that HSCs contain mitochondria with low levels of activity. This is supported by a lower respiratory rate and a low mitochondrial membrane potential when compared with downstream progenitors (Du et al, 2014;Simsek et al, 2010). The difference in mitochondrial membrane potential between ESCs and HSCs may represent the proliferative and 'primed to differentiate' nature of ESCs, in contrast to HSCs (which are mostly quiescent).…”