Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites.

Kenneth K Wu

doi:10.3390/ijms22020697

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.

Highlights

Cellular senescence is a hallmark of aging [1]
Recent studies indicate that tryptophan metabolites produced via the tryptophan hydroxylase (TPH) pathway defend against replicative and hyperglycemia or oxidative stress-induced cell senescence. 5-methoxytryptophan (5-MTP) was reported to rescue bone marrow mesenchymal stromal cells (BM-mesenchymal stromal/stem cell (MSC)) from high glucose (HG)induced senescence [22], while melatonin protects MSC from replicative and stress-induced senescence [23]
Fibroblasts express only HIOMT298 isoform which was shown to be active in catalyzing 5-MTP synthesis [58]

Summary

Introduction

Cellular senescence is a hallmark of aging [1]. Accumulation of senescent cells promotes aging and triggers age-related disorders [2]. Cellular senescence was originally observed in cultured fibroblasts following limited replications [3]. It was subsequently noted as a response to DNA damage, telomere attrition, mitochondrial dysfunction, and oncogenic, hyperglycemic, and oxidative stresses [4,5,6]. Replicative and stress (hyperglycemia and oxidative stress)-induced mesenchymal stromal cell senescence has been extensively investigated as it is critical for MSC-based cell therapy. Recent studies indicate that tryptophan metabolites produced via the tryptophan hydroxylase (TPH) pathway defend against replicative and hyperglycemia or oxidative stress-induced cell senescence. Melatonin and 5-MTP represent a new class of senomorphic compounds which may be useful in protecting MSC against senescence and age-related diseases. This review will comment on the anti-senescence actions of 5-MTP and melatonin with a focus on 5-MTP biosynthesis, its defense of HG-induced MSC senescence, and mechanisms of actions

Hyperglycemia Induces Cellular Senescence

Melatonin Protects Against Replicative and Stress-Induced Cellular Senescence

Melatonin and 5-MTP Control Cellular Senescence through Inhibition of NF-κB

Conclusions