Aspirin induces apoptosis in mesenchymal stem cells requiring Wnt/β-catenin pathway

Authors

  • L. Deng,

    1. Research Center for Cardiovascular Regenerative Medicine, Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, Beijing 100037, China
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  • S. Hu,

    1. Research Center for Cardiovascular Regenerative Medicine, Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, Beijing 100037, China
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  • A. R. Baydoun,

    1. School of Life Science, Faculty of Health and Human Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
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  • J. Chen,

    1. Research Center for Cardiovascular Regenerative Medicine, Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, Beijing 100037, China
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  • X. Chen,

    1. Research Center for Cardiovascular Regenerative Medicine, Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, Beijing 100037, China
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  • X. Cong

    1. Research Center for Cardiovascular Regenerative Medicine, Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, Beijing 100037, China
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X. Chen and X. Cong, Research, Center for Cardiovascular Regenerative Medicine, Ministry of Health, and Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Science & Peking Union Medicine College, 167 Beilishilu, Beijing 100037, China. Tel.: +86 10 88398584; Fax: +86 10 88398584; E-mail: chenxifw@yahoo.com.cn and xiangfeng_cong@yahoo.com.cn

Abstract

Background and Objectives:  Mesenchymal stem cells (MSC) are multipotent progenitor cells that are have found use in regenerative medicine. We have previously observed that aspirin, a widely used anti-inflammatory drug, inhibits MSC proliferation. Here we have aimed to elucidate whether aspirin induces MSC apoptosis and whether this is modulated through the Wnt/β-catenin pathway.

Materials and methods:  Apoptosis of MSCs was assessed using Hoechst 33342 dye and an Annexin V–FITC/PI Apoptosis Kit. Expression of protein and protein phosphorylation were investigated using Western blot analysis. Caspase-3 activity was detected by applying a caspase-3/CPP32 Colorimetric Assay Kit.

Results:  In these MSCs, aspirin induced morphological changes characteristic of apoptosis, cytochrome c release from mitochondria, and caspase-3 activation. Stimulating the Wnt/β-catenin pathway by both Wnt 3a and GSK-3β inhibitors (LiCl and SB 216763), blocked aspirin-induced apoptosis and protected mitochondrial function, as demonstrated by decreased cytochrome c release and caspase-3 activity. Aspirin initially caused a time-dependent decrease in COX-2 expression but subsequently, and unexpectedly, elevated the latter. Stimulation of COX-2 expression by aspirin was further enhanced following stimulation of the Wnt/β-catenin pathway. Application of the COX-2 inhibitor NS-398 suppressed elevated COX-2 expression and promoted aspirin-induced apoptosis.

Conclusion:  These results demonstrate that the Wnt/β-catenin pathway is a key modulator of aspirin-induced apoptosis in MSCs by regulation of mitochrondrial/caspase-3 function. More importantly, our findings suggest that aspirin may influence MSC survival under certain conditions; therefore, it should be used with caution when considering regenerative MSC transplantation in patients with concomitant chronic inflammatory diseases such as arthritis.

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