Research ArticleStem Cells

Kynurenine signaling through the aryl hydrocarbon receptor maintains the undifferentiated state of human embryonic stem cells

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Science Signaling  25 Jun 2019:
Vol. 12, Issue 587, eaaw3306
DOI: 10.1126/scisignal.aaw3306

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Kynurenine metabolism in embryonic stem cells

Kynurenine, a tryptophan metabolite generated by the enzyme IDO1, is a ligand for the aryl hydrocarbon receptor (AhR). Yamamoto et al. found that IDO1, kynurenine, and the AhR were required for self-renewal and for AhR-mediated expression of self-renewal genes in undifferentiated human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Kynurenine synthesis was required for maintenance of the undifferentiated state in ESCs, and the degradation of kynurenine was required for ESCs to undergo ectodermal differentiation. In addition to identifying kynurenine metabolism as an important factor in ESC maintenance and ectodermal differentiation, these findings show that the secretion of kynurenine and the kynurenine catabolite 2-AAA are biomarkers for undifferentiated stem cells and nascent ectoderm, respectively.

Abstract

Kynurenine, which is generated from tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1), binds to the aryl hydrocarbon receptor (AhR). Here, we report that kynurenine was produced by undifferentiated human embryonic stem cells (hESCs) and by induced pluripotent stem cells (iPSCs). In undifferentiated hESCs, kynurenine stimulated the AhR to promote the expression of self-renewal genes. The kynurenine-AhR complex also stimulated the expression of IDO1 and AHR, activating a positive feedback loop. Inhibition of IDO1 activity reduced the proliferation of undifferentiated ESCs but did not stimulate their differentiation. Substantial amounts of free kynurenine were present in the culture medium, providing a paracrine signal for maintenance of the undifferentiated state. Kynurenine was not present in the medium of differentiated ESCs or iPSCs. When ESCs were induced to undergo ectodermal differentiation, the abundance of kynurenine in the medium was reduced through activation of the main kynurenine catabolic pathway mediated by kynurenine aminotransferase 2 (KAT2, also known as AADAT), resulting in the secretion of 2-aminoadipic acid (2-AAA) into the culture medium. Inhibition of KAT2 activity blocked ectodermal differentiation. Thus, kynurenine metabolism plays an important role in the maintenance of the undifferentiated state and in ectodermal differentiation. Furthermore, kynurenine in the culture medium is a biomarker for the undifferentiated state, whereas the presence of 2-AAA in the culture medium is a biomarker of ESCs and iPSCs that have committed to differentiate along the ectoderm lineage.

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