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Estrogen Controls embryonic stem cell proliferation via store-operated calcium entry and the nuclear factor of activated T-cells (NFAT)

Authors

  • Chun-Kit Wong,

    1. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Wing-Yan So,

    1. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Sau-Kwan Law,

    1. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Fung-Ping Leung,

    1. Li Ka Shing Institute of Health Sciences, Institute of Vascular Medicine and School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Ka-Long Yau,

    1. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Xiaoqiang Yao,

    1. Li Ka Shing Institute of Health Sciences, Institute of Vascular Medicine and School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Yu Huang,

    1. Li Ka Shing Institute of Health Sciences, Institute of Vascular Medicine and School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
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  • Xiangdong Li,

    1. State Key Laboratory of Agrobiotechnology, China Agricultural University, Hong Kong, China
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  • Suk-Ying Tsang

    Corresponding author
    1. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
    2. State Key Laboratory of Agrobiotechnology, Chinese University of Hong Kong, Hong Kong, China
    3. Stem Cell and Regeneration Program, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
    4. Key Laboratory for Regenerative Medicine, Ministry of Education, Chinese University of Hong Kong, Hong Kong, China
    • School of Life Sciences, Chinese University of Hong Kong, Rm 607, Mong Man Wai Building, Shatin, N.T., Hong Kong, China.
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  • Author contributions: Chun-Kit Wong: Collection, analysis and interpretation of data; drafting the article. Wing-Yan So: Collection, analysis and interpretation of data; drafting the article. Sau-Kwan Law: Collection, analysis and interpretation of data. Fung-Ping Leung: Collection, analysis and interpretation of data. Ka-Long Yau: Collection, analysis and interpretation of data. Xiaoqiang Yao: Conception and design of the experiments; revising the article critically for important intellectual content. Yu Huang: Conception and design of the experiments; revising the article critically for important intellectual content. Xiangdong Li: Conception and design of the experiments; revising the article critically for important intellectual content. Suk-Ying Tsang: Conception and design of the experiments; collection, analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; Administrative support.

Abstract

Embryonic stem cells (ESCs) can self-renew indefinitely and differentiate into all cell lineages. Calcium is a universal second messenger which regulates a number of cellular pathways. Previous studies showed that store-operated calcium channels (SOCCs) but not voltage-operated calcium channels are present in mouse ESCs (mESCs). In this study, store-operated calcium entry (SOCE) was found to exist in mESCs using confocal microscopy. SOCC blockers lanthanum, 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365 reduced mESC proliferation in a concentration-dependent manner, suggesting that SOCE is important for ESC proliferation. Pluripotent markers, Sox-2, Klf-4, and Nanog, were down-regulated by 2-APB, suggesting that self-renewal property of mESCs relies on SOCE. 17β-estradiol (E2) enhanced mESC proliferation. This enhanced proliferation was associated with an increment of SOCE. Both stimulated proliferation and increased SOCE could be reversed by SOCC blockers suggesting that E2 mediates its stimulatory effect on proliferation via enhancing SOCE. Also, cyclosporin A and INCA-6, inhibitors of calcineurin [phosphatase that de-phosphorylates and activates nuclear factor of activated T-cells (NFAT)], reversed the proliferative effect of E2, indicating that NFAT is involved in E2-stimulated proliferation. Interestingly, E2 caused the nuclear translocation of NFATc4, and this could be reversed by 2-APB. These results suggested that NFATc4 is the downstream target of E2-induced SOCE. The present investigation provides the first line of evidence that SOCE and NFAT are crucial for ESCs to maintain their unique characteristics. In addition, the present investigation also provides novel information on the mechanisms of how E2, an important female sex hormone, affects ESC proliferation. J. Cell. Physiol. 227: 2519–2530, 2012. © 2011 Wiley Periodicals, Inc.

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