Fucoxanthin protects placenta-derived human mesenchymal stem cells against oxidative stress-induced apoptosis by modulating genes involved in DNA damage repair, ER stress response, p53-induced apoptosis

Abstract

Human mesenchymal stem cells (hMSCs) hold significant promise in regenerative medicine due to their ability to reduce inflammation and promote tissue repair. However, their therapeutic potential is often compromised by their high susceptibility to apoptosis under oxidative stress, prevalent in the microenvironment of the target tissues. Our previous study showed that fucoxanthin, a carotenoid derived from brown algae, can improve the viability of placenta-derived mesenchymal stem cells (PL-MSCs) by reducing intracellular ROS levels through the activation of the PI3K/Akt/Nrf-2 signaling pathway. In this study, we further investigate the mechanisms underlying the protective effect of fucoxanthin against oxidative stress-induced apoptosis in PL-MSCs, using an in vitro model. PL-MSCs were cultured with 750 µM H2O2 to induce oxidative stress and treated with various concentrations of fucoxanthin for 48 h. The effect of fucoxanthin on PL-MSC apoptosis under oxidative stress conditions was determined using CCK-8, Annexin V/DRAQ7™ apoptosis assays, as well as the expression of apoptosis-related genes and proteins. The effect of fucoxanthin on the transcriptome of PL-MSCs under oxidative stress conditions was also assessed by high-throughput Nanostring analysis. The results showed that fucoxanthin significantly decreased the apoptosis of PL-MSCs under oxidative stress in a dose-dependent manner by reducing the expression of pro-apoptotic proteins and inhibiting their activation, while increasing the expression of anti-apoptotic proteins in these cells. Furthermore, fucoxanthin also downregulates the expression of genes associated with the endoplasmic reticulum stress, p53-induced apoptosis, while increasing the expression of genes involved in the regulation of the cell cycle, DNA damage repair, cytokine signaling, nucleotide synthesis, PI3K/mTOR pathway and AMPK pathway in PL-MSCs under oxidative stress conditions. Taken together, the findings provide compelling evidence that fucoxanthin protects PL-MSCs against oxidative stress-induced apoptosis by modulating the expression of various genes involved in DNA damage repair, ER stress response, p53-induced apoptosis in these cells. This suggests that fucoxanthin could be used as a potential supplement to enhance the therapeutic efficacy of MSC-based therapies.

1. Introduction

Human mesenchymal stem cells (hMSCs) could potentially be used in cell-based therapies due to their ability to home in on specific tissues and release various beneficial factors to reduce inflammation and promote tissue repair [1, 2]. However, there is evidence indicating that most MSCs undergo apoptosis shortly after being introduced into the target tissues [3, 4]. The poor viability of grafted MSCs is largely due to oxidative stress caused by an excessive amount of reactive oxygen species (ROS) in target tissues [5]. Oxidative stress has been shown to inhibit proliferation, increase senescence, and induce apoptosis in transplanted MSCs by damaging their cellular components [6].

Fucoxanthin, a marine carotenoid derived from edible brown algae, is known for its strong antioxidant properties that provide various health benefits, including anti-obesity [7], anti-cancer [8] and anti-inflammation [9] effects. Previous studies indicate that fucoxanthin significantly increases glutathione levels, reduces ROS, inhibits DNA damage, restores mitochondrial membrane potential and suppresses apoptosis in human keratinocytes [10, 11], retinal pigment epithelial cells [12, 13] and neurons [14] under oxidative stress conditions. Furthermore, our previous study found that fucoxanthin also protects human placenta-derived mesenchymal stem cells (PL-MSCs) from oxidative stress by reducing intracellular ROS production and improving their viability by activating the PI3K/Akt/Nrf-2 signaling pathway [15].

However, the effect of fucoxanthin on the prevention of MSC apoptosis under oxidative stress conditions has not yet been determined. Therefore, in this study, we further investigate the mechanisms underlying the protective effect of fucoxanthin against oxidative stress-induced apoptosis in PL-MSCs. We use PL-MSCs, which can be harvested in large quantities and have shown promise in regenerative medicine.