IDO1 Maintains Pluripotency of Primed Human Embryonic Stem Cells by Promoting Glycolysis

Abstract

Human embryonic stem cells (hESCs) depend on glycolysis for energy supply and pluripotency and switch to oxidative phosphorylation upon differentiation. The underlying mechanisms remain unclear. Here, we demonstrate that indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in primed hESCs and its expression rapidly downregulated upon hESC differentiation. IDO1 is required to maintain pluripotency by suppressing mitochondria activity and promoting glycolysis through the increase of NAD + /NADH ratio. The upregulation of IDO1 during hESC differentiation suppresses the differentiation of hESCs into certain lineages of cells such as cardiomyocytes, which depend on oxidative phosphorylation to satisfy their high energy demand. Therefore, IDO1 plays important roles in maintaining the pluripotency of hESCs.Indoleamine 2,3-dioxygenase 1 (IDO1) has been known to play important metabolic roles in the kynurenine pathway. This study discovered that IDO1 is required to maintain glycolysis in human embryonic stem cells (hESCs), and therefore maintains pluripotency of hESCs. These findings further shed light on the link between pluripotency and cancer, since cancer cells have a similar metabolic process as stem cells.

Nicotinamide adenine dinucleotide induces a bivalent metabolism and maintains pluripotency in human embryonic stem cells

“…NAD + regulation has been shown to be necessary for both the acquisition and maintenance of human and mouse ESC pluripotency . In hESCs, a 50% reduction in NAD + by inhibiting nicotinamide phosphoribosyltransferase (NAMPT) activity causes spontaneous differentiation and apoptosis .…”

“…pluripotency. [17][18][19] In hESCs, a 50% reduction in NAD + by inhibiting nicotinamide phosphoribosyltransferase (NAMPT) activity causes spontaneous differentiation and apoptosis. 20 Furthermore, ESCs and induced pluripotent stem cells (iPSCs) are reliant on, and have higher levels of, NAD + salvage enzymes compared with their differentiated counterparts.…”

Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells

“…Liu et al recently reported that IDO1 mediated the maintenance of pluripotency in human embryonic stem cells [ 26 ] and led us to investigate the potential regulatory activity of IDO1 in Notch1 expression. With the lentiviral delivery of IDO1 specific shRNAs ( Figure 5 A) or the treatment of INCB-024360 ( Figure 5 B), the inhibition of IDO1 in HeLa and SiHa tumorspheres caused the downregulation of NICD.…”

Epigenetic Alterations under Oxidative Stress in Stem Cells

“…Similarly, suppression of mitochondrial respiration is beneficial to maintain the pluripotency. Indeed, either promotion of glycolysis or suppression of oxidative phosphorylation can accelerate the reprogramming process during which somatic cells are converted into induced pluripotent stem cells (iPSCs) [ 44 ]. Considering the hypoxic condition in the uterus, it is not surprising that ESCs—the in vitro counterpart of inner cell mass in the early embryo—prefer glycolysis.…”