Co-Administration of Melatonin Effectively Enhances the Therapeutic Effects of Pioglitazone on Mesenchymal Stem Cells Undergoing Indoxyl Sulfate-Induced Senescence through Modulation of Cellular Prion Protein Expression

Abstract

Background: Mesenchymal stem cells (MSCs) are a promising source for regenerative medicine. However, their therapeutic potential in patients with chronic kidney disease (CKD) is restricted by the presence of uremic toxins. To address this limitation, we explored the protective effect of melatonin and pioglitazone on MSCs undergoing senescence induced by the uremic toxin, indoxyl sulfate (IS). Methods: MSC senescence was induced by IS, and the therapeutic effects of melatonin and pioglitazone were identified. The expression of cellular prion protein (PrPC) was suppressed by transfection of MSCs with prion protein gene (PRNP) siRNA. Subsequently, these cells were used to study the protective effects of melatonin and pioglitazone against IS-induced senescence; Results: The IS-induced senescence of MSCs was significantly reduced by co-treatment with melatonin and pioglitazone compared to treatment with melatonin or pioglitazone alone. In the presence of IS, the reduced MSC proliferation was rescued by co-treatment with melatonin and pioglitazone. Melatonin and pioglitazone enhanced the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) in MSCs, which resulted in the augmentation of PrPC level. The inhibitory effect of the co-treatment with melatonin and pioglitazone on IS-induced senescence in MSCs was blocked by the knockdown of PRNP. In addition, the restorative effect of the co-treatment on the reduced MSC proliferation induced by IS was also blocked by the knockdown of PRNP. These findings indicate that co-treatment with melatonin and pioglitazone protected MSCs from uremic toxin-induced senescence through the regulation of the PPAR-γ-PrPC axis. Conclusions: Our study suggests that co-treatment of MSCs with melatonin and pioglitazone may represent a novel strategy for the development of MSC-based therapies for patients with CKD.

Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC‐dependent enhancement of the mitochondrial function

“…We previously reported that melatonin enhances MSC viability and motility, stemness, and proliferation and inhibits senescence induced by uremic toxins accumulated in CKD, thereby inducing the proliferation of MSC . In addition, melatonin treatment of MSCs also effectively allows cells to withstand the pathophysiological conditions of the environment near the ischemic engraftment site via precise mechanisms such as the induction of antioxidant enzymes and proangiogenic cytokines .…”

Melatonin‐stimulated exosomes enhance the regenerative potential of chronic kidney disease‐derived mesenchymal stem/stromal cells via cellular prion proteins

“…CKD induces the progressive loss of function in kidneys resulting in ineffective homeostasis in the body. CKD‐induced uremic toxins, such as indoxyl sulfate and p‐cresol, hamper the biological activities of MSCs and lead to cardiovascular disease, weakened bones, malfunctioning central nervous system, and improper inflammation in patients . The regenerative potential of CKD‐MSCs is also suppressed in a murine ischemic injury .…”

“…system, and improper inflammation in patients. 12,13 The regenerative potential of CKD-MSCs is also suppressed in a murine ischemic injury. 10,14 Consistent with these findings, our results have shown that biological functions like senescence, proliferation, and mitochondrial activity were significantly decreased in CKD-MSCs and treatment with MT exosomes drastically improved these CKD-mediated pathophysiological conditions.…”

Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1

“…Pioglitazone, as a peroxisome proliferator-activated receptor-gamma (PPAR-γ), reduced apoptosis of bone marrow endothelial progenitor cells via the PI3K–Akt signal axis [ 30 ]. Our previous findings have revealed that pioglitazone protects against the uremic toxin, indoxyl-sulfate-induced cellular senescence in MSCs through the PPAR-γ–cellular prion protein signal pathway [ 31 ]. These findings suggest that pioglitazone protects against PC-induced apoptosis in MSCs through the regulation of apoptosis-associated proteins.…”