Abstract
The kynurenine pathway (KP) of tryptophan metabolism is linked to antimicrobial activity and modulation of immune responses but its role in stem cell biology is unknown. We show that human and mouse mesenchymal and neural stem cells (MSCs and NSCs) express the complete KP, including indoleamine 2,3 dioxygenase 1 (IDO) and IDO2, that it is highly regulated by type I (IFN-β) and II interferons (IFN-γ), and that its transcriptional modulation depends on the type of interferon, cell type and species. IFN-γ inhibited proliferation and altered human and mouse MSC neural, adipocytic and osteocytic differentiation via the activation of IDO. A functional KP present in MSCs, NSCs and perhaps other stem cell types offers novel therapeutic opportunities for optimisation of stem cell proliferation and differentiation.
Highlights
In mammalian tissues and organs, including the brain, the kynurenine pathway (KP) is the central route that accounts for the degradation of the essential amino acid tryptophan (Trp) and generates the ubiquitous co-factor nicotinamide adenine dinucleotide (NAD+), which participates in basic cellular processes [1]
IDO2 is structurally similar to IDO1; it can use a similar range of substrates but differs in the selectivity for some IDO inhibitors [4,5] - norharmane is IDO1- and IDO2specific, while L- and D-isomers of 1-methyl tryptophan inhibitors are specific of IDO1 and IDO2 respectively
We showed that mouse and human Mesenchymal stem cells (MSCs) express the complete, functional KP enzymatic machinery, including IDO1 and its recently identified paralogue IDO2 [4,5], and that the expression of the KP enzymes is highly regulated by both type I and II interferons i.e. IFN-b and IFN-c respectively
Summary
In mammalian tissues and organs, including the brain, the kynurenine pathway (KP) is the central route that accounts for the degradation of the essential amino acid tryptophan (Trp) and generates the ubiquitous co-factor nicotinamide adenine dinucleotide (NAD+), which participates in basic cellular processes [1]. Named after a pivotal metabolite, kynurenine (KYN), the KP is a metabolic cascade of enzymatic steps, which yields several neuroactive compounds including quinolinic acid (QUIN), an Nmethyl-D-aspartate (NMDA) receptor agonist that has neurotoxic effects [1]. The levels of these metabolites are determined by several KP enzymes, which in the brain are primarily contained in microglial cells and astrocytes (Fig. S1) [2]. Unlike IDO, TDO does not respond to immunological signals and is primarily but not exclusively confined to the liver (for review [10])
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