Abstract
Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P-cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) regulated the pioglitazone-mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF-κB–PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD.
Highlights
Mesenchymal stem cells (MSCs) are a promising source of stem-cell-based therapeutics for regenerative medicine because they have the potential for self-renewal and multipotent differentiation [1]
This study has shown that pretreatment of MSCs with pioglitazone restored mitochondrial potential, and increased activation of complexes I/IV and mitophagy through up-regulation of Phosphatase and tensin homolog-induced kinase 1 (PINK-1) under PC exposure conditions
These findings suggest that pretreatment of MSCs with pioglitazone could enhance stem cell therapy for Chronic kidney disease (CKD) patients with high levels of uremic compounds
Summary
Mesenchymal stem cells (MSCs) are a promising source of stem-cell-based therapeutics for regenerative medicine because they have the potential for self-renewal and multipotent differentiation [1]. MSC transplantation has shown therapeutic efficacy in several disease models, such as myocardial infarction, hind limb ischemia, wound healing, and stroke, owing to their potential for expansion, differentiation, and secretion of cytokines [2]. MSCs have a high therapeutic potential for regenerative diseases, their transplantation and therapeutic efficacy are limited by the pathophysiological conditions in damaged sites. Oxidative stress, ischemia, and inflammation lead to dysfunction and affect the survival of transplanted MSCs, resulting in the cell death of transplanted cells in the targeted area [3,4]. To promote the therapeutic effects of MSCs in various diseases, it is important to improve the survival of engrafted MSCs in damaged sites by endowing them with resistance to these pathophysiological conditions. It is important to enhance MSC functionality against uremic toxins for successful MSC-based therapy in CKD patients
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