Abstract
Human mesenchymal stem cells (hMSCs) are a potent source of cell-based regenerative therapeutics used to treat patients with ischemic disease. However, disease-induced oxidative stress disrupts mitochondrial homeostasis in transplanted hMSCs, resulting in hMSC apoptosis and reducing their efficacy post-transplantation. To address this issue, we evaluated the effects of melatonin on cellular defense mechanisms and mitophagy in hMSCs subjected to oxidative stress. H2O2-induced oxidative stress increases the levels of reactive oxygen species and reduces membrane potential in hMSCs, leading to mitochondrial dysfunction and cell death. Oxidative stress also decreases the expression of 70-kDa heat shock protein 1L (HSPA1L), a molecular chaperone that assists in the recruitment of parkin to the autophagosomal mitochondrial membrane. Decreased expression of HSPA1L destabilizes parkin, thereby impairing mitophagy. Our results indicate that treating hMSCs with melatonin significantly inhibited mitochondrial dysfunction induced by oxidative stress, which decreased hMSCs apoptosis. In damaged hMSCs, treatment with melatonin increased the levels of HSPA1L, which bound to parkin. The interaction between HSPA1L and parkin increased membrane potential and levels of oxidative phosphorylation, resulting in enhanced mitophagy. Our results indicate that melatonin increased the expression of HSPA1L, thereby upregulating mitophagy and prolonging cell survival under conditions of oxidative stress. In this study, we have shown that melatonin, a readily available compound, can be used to improve hMSC-based therapies for patients with pathologic conditions involving oxidative stress.
Highlights
Human mesenchymal stem cells, which are present mainly in the bone marrow, adipose tissue, dental pulp, and the umbilical cord, can potentially be used in cell-based therapies and regenerative medicine because of their continued self-renewal, multidirectional differentiation, and immunomodulatory abilities [1,2,3]
Our results indicate that the viability of Human mesenchymal stem cells (hMSCs) was reduced by approximately 50% at 4 h post-treatment with H2O2
Our findings show that oxidative stress caused a significant accumulation of impaired mitochondria in hMSCs treated with 200 μM H2O2 for 4 h
Summary
Human mesenchymal stem cells (hMSCs), which are present mainly in the bone marrow, adipose tissue, dental pulp, and the umbilical cord, can potentially be used in cell-based therapies and regenerative medicine because of their continued self-renewal, multidirectional differentiation, and immunomodulatory abilities [1,2,3]. Mitochondria play an important role in ATP synthesis during aerobic respiration In this process, reactive oxygen species (ROS), such as the superoxide anion (O2−), hydroxyl radicals (OH−), hydroperoxyl (HO2−), and hydrogen peroxide (H2O2), are formed as metabolites of mitochondrial oxidative phosphorylation [9,11,12]. Under conditions of oxidative stress, mitochondria can synthesize ROS at a level that extensively disrupts mitochondrial homeostasis, altering the composition of lipids, proteins, and nucleic acids. Melatonin (N-acetyl-5-methoxytryptamine) is synthesized from serotonin and is the main hormone secreted by the pineal gland at night under normal light/dark conditions It was first discovered and isolated from the bovine pineal gland by Aaron Lerner [19]. We examined whether enhanced interactions between HSPA1L and parkin underlie melatonin-enhanced mitophagy and resulting reduction in oxidative stress
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