A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

Benjamin Sebastian Summers; Sarah Thomas Broome; Tsz Wai Rosita Pang; Hamish D Mundell; Naomi Koh Belic; Nicole C Tom; Mei Li Ng; Maylin Yap; Monokesh K Sen; Sara Sedaghat; Michael W Weible; Alessandro Castorina; Chai K Lim; Michael D Lovelace; Bruce J Brew

doi:10.1177/11786469241248287

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

Int J Tryptophan Res. 2024 May 15:17:11786469241248287. doi: 10.1177/11786469241248287. eCollection 2024.

Authors

Benjamin Sebastian Summers^{1

2}, Sarah Thomas Broome³, Tsz Wai Rosita Pang⁴, Hamish D Mundell⁵, Naomi Koh Belic⁶, Nicole C Tom⁷, Mei Li Ng⁸, Maylin Yap⁹, Monokesh K Sen^{1

10

11}, Sara Sedaghat¹², Michael W Weible^{13

14}, Alessandro Castorina³, Chai K Lim¹⁵, Michael D Lovelace^{1

2}, Bruce J Brew^{1

2

16

17}

Affiliations

¹ Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia.
² Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia.
³ Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia.
⁴ Faculty of Medicine and Health, The University of Sydney, NSW, Australia.
⁵ Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia.
⁶ School of Life Sciences, University of Technology, Sydney, NSW, Australia.
⁷ Formerly of the Department of Physiology, University of Sydney, NSW, Australia.
⁸ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁹ Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
¹⁰ School of Medicine, Western Sydney University, NSW, Australia.
¹¹ Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia.
¹² Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
¹³ School of Environment and Science, Griffith University, Brisbane, QLD, Australia.
¹⁴ Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.
¹⁵ Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
¹⁶ Departments of Neurology and Immunology, St. Vincent's Hospital, Sydney, NSW, Australia.
¹⁷ University of Notre Dame, Darlinghurst, Sydney, NSW, Australia.

Abstract

Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.

Keywords: IDO-1; TDO2; Tryptophan metabolism; aryl hydrocarbon receptor; cancer stem cells; hematopoietic stem cells; human diseases; induced pluripotent stem cells; kynurenine pathway; mesenchymal stromal cells; neural stem cells.

Publication types

Review