PDF(Pubmed)
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.
摘要：
干细胞普遍存在于体内的各种组织和器官中，并支撑身体在受伤或疾病引发后自我修复的能力，虽然修复有时会受到影响。了解干细胞是如何产生的，不同生态位之间的功能信号系统对于理解干细胞在再生医学中的潜在用途至关重要。在这种情况下，这篇综述认为犬尿氨酸途径（KP）在多能成人祖细胞中的代谢，胚胎,造血，神经,癌症,心脏和诱导多能干细胞，内皮祖细胞，和间充质基质细胞。KP是顺序分解代谢必需氨基酸色氨酸（TRP）的主要酶促途径，产生包括犬尿氨酸在内的关键代谢物，犬尿酸,和喹啉酸（QUIN）。QUIN代谢过渡到烟酰胺腺嘌呤二核苷酸（NAD）生产的邻接从头途径，许多基本细胞生化途径中的关键辅因子。干细胞摄取和利用TRP的方式在不同物种和干细胞类型之间有所不同。因为它们的转运蛋白表达和对炎症细胞因子的反应。几种KP代谢物具有生理活性，无论是有益的还是有害的结果，并提出了与几种干细胞类型有关的证据，这很重要，因为它们可能对周围的分化细胞产生重大影响，特别是如果它们代谢或分泌代谢物不同。间充质基质细胞中的干扰素-γ（IFN-γ），例如,高度上调限速酶吲哚胺-2,3-双加氧酶（IDO-1），启动TRP消耗和代谢物的生产，包括犬尿氨酸/犬尿氨酸，已知的芳香烃受体(AhR)转录因子的激动剂。AhR转录调节免疫抑制表型，使它们对再生治疗有吸引力。我们还提请注意未来研究的重要知识差距，这将支持基于干细胞的细胞疗法的未来应用或优化可以调节先天干细胞群体中KP的药物，用于疾病治疗。
