Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

Abstract

Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…As a reduction in melatonin secretion has been observed during aging [ 452 ], several studies have explored the role of this hormone in counteracting cellular senescence [ 451 ]. In this respect, melatonin has been proven capable of reducing oxidative stress and replicative senescence by enhancing autophagy, activating AMPK/FOXO3 pathways and increasing mitochondrial membrane potential, both in vitro and in vivo [ 455 , 456 , 457 ]. Melatonin-induced decrease in p53, p21 and p16 proteins, together with enhanced SIRT1 activity, have also been reported in the context of H 2 O 2 -induced senescence [ 458 , 459 ].…”

MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism

“…In MSCs the activation of IDO in response to inflammatory factors is triggering immunosuppression as a result of tryptophan depletion causing apoptosis of T cells, inhibition of T cells and NK cells proliferation, inhibition of DCs maturation, and induction of Treg immune suppressor cells (174). On the other hand, tryptophan metabolites from the tryptophan hydroxylase (TPH) pathway (5-methoxytryptophan, melatonin) protect MSCs against replicative and oxidative stress-induced senescence (175). The amino acid arginine is catalyzed by enzymes highly regulated by the inflammatory setting leading to opposite immunological consequences in myeloid cells.…”

PTSD as an Endothelial Disease: Insights From COVID-19

“…In addition, tryptophan 5-hydroxylase 2 (TPH2), an enzyme involved in serotonin synthesis, was found to have a strong mimicry with the S protein of SARS-CoV-2, potentially contributing to anxiety and depression (Yapici-Eser et al, 2021). This is significant as TPH2 plays a major role in PTSD, as well as in premature ECs senescence (Goçi Uka et al, 2019;Wu, 2021). Moreover, the molecular mimicry between the SARS-CoV-2 protein S and human anti-inflammatory proteins was associated with inflammation, a pathology demonstrated in PTSD (Kanduc, 2020).…”