Dataset Information

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

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.

SUBMITTER: Yoon YM

PROVIDER: S-EPMC6213327 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Pioglitazone Protects Mesenchymal Stem Cells against <i>P</i>-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1.

Yoon Yeo Min YM Han Yong-Seok YS Yun Chul Won CW Lee Jun Hee JH Kim Rang R Lee Sang Hun SH

International journal of molecular sciences 20180924 10

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 <i>P</i>-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 mito ...[more]

PMID: 30250007

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Project description:Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

Dataset Information

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

Publications

Pioglitazone Protects Mesenchymal Stem Cells against <i>P</i>-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1.

Similar Datasets

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