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Peroxisome Proliferator-Activated Receptor Gamma Promotes Mesenchymal Stem Cells to Express Connexin43 via the Inhibition of TGF-β1/Smads Signaling in a Rat Model of Myocardial Infarction

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Abstract

Background

In this study, we hypothesized that activation of PPAR-γ enhanced MSCs survival and their therapeutic efficacy via upregulating the expression of Cx43.

Methods

MI was induced in 50 male Sprague–Dawley rats. The rats were randomized into five groups: MI group and four intervention groups, including the MSCs group, combined therapy group (MSCs+ pioglitazone), pioglitazone group and PBS group. Two weeks later, 5 × 106 MSCs labeled with PKH26 in PBS were injected into the infarct anterior ventricular free wall in the MSCs and combined therapy groups, and PBS alone was injected into the infarct anterior ventricular free wall in the PBS group. Pioglitazone (3 mg/kg/day) was given to the combined therapy and pioglitazone groups by oral gavage at the same time for another 2 weeks. Myocardial function and relevant signaling molecules involved were all examined thereafter.

Results

Heart function was enhanced after MSCs treatment for 2 weeks post MI. A significant improvement of heart function was observed in the combined therapy group in contrast to the other three intervention groups. Compared with the MSCs group, there was a higher level of PPAR-γ in the combined therapy group; Cx43 was remarkably increased in different regions of the left ventricle; TGF-β1 was decreased in the infarct zone and border zone. To the downstream signaling molecules, mothers against Smad proteins including Smad2 and Smad3 presented a synchronized alteration with TGF-β1; no differences of the expressions of ERK1/2 and p38 could be discovered in the left ventricular cardiac tissue.

Conclusions

MSCs transplantation combined with pioglitazone administration improved cardiac function more effectively after MI. Activation of PPAR-γ could promote MSCs to express Cx43. Inhibition of TGF-β1/Smads signaling pathway might be involved in the process.

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Abbreviations

MSCs:

Mesenchymal Stem Cells

PPAR-γ:

Peroxisome Proliferator-activated Receptor Gamma Cx43 Connexin 43

TGF-β1:

Transforming growth factor beta-1

Smad:

Decapentaplegic homolog proteins

ERK:

Extracellular signal-regulated kinase

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Acknowledgments

This study was supported by Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology; Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes; National Natural Science Foundation of China (No: 81070125, 81270213), Science and Technology Foundation in Guangdong Province (No: 2010B031600032, 2014A020211002) and the Fundamental Research Funds for the Central Universities (13ykzd16).

Conflict of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

This work was done by the investigators of the Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The authors took responsibility for all aspects of the reliability and had no differences in data presentation and interpretation. Jingying Hou and Linyun Wang carried out the experiments and drafted the manuscript; Yue Xing, Tianzhu Guo, Shaoxin Zheng and Changqing Zhou participated in the preparation of the animal model, tissue staining, and molecular assay; Jinghui Hou, Hui Huang and Jingfeng Wang provided the technical assistance; Huibao Long, Tingting Zhong and Quanhua Wu participated the statistical analysis; Tong Wang conceived the study and participated in the study design. All the authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120

    Jingying Hou, Lingyun Wang, Jinghui Hou, Tianzhu Guo, Yue Xing, Shaoxin Zheng, Changqing Zhou, Hui Huang, Huibao Long, Tingting Zhong, Quanhua Wu, Jingfeng Wang & Tong Wang

  2. Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China

    Shaoxin Zheng, Hui Huang & Tong Wang

  3. Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China

    Jingfeng Wang & Tong Wang

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  1. Jingying Hou
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  2. Lingyun Wang
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  3. Jinghui Hou
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  4. Tianzhu Guo
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  5. Yue Xing
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  13. Tong Wang
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Corresponding author

Correspondence to Tong Wang.

Additional information

Dr. Jingying Hou and Dr. Lingyun Wang played equally important roles in the development of the experimental protocol in the interpretation of the results, and in the texture of the present article.

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Hou, J., Wang, L., Hou, J. et al. Peroxisome Proliferator-Activated Receptor Gamma Promotes Mesenchymal Stem Cells to Express Connexin43 via the Inhibition of TGF-β1/Smads Signaling in a Rat Model of Myocardial Infarction. Stem Cell Rev and Rep 11, 885–899 (2015). https://doi.org/10.1007/s12015-015-9615-7

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