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The effects of mesenchymal stem cells on c-kit up-regulation and cell-cycle re-entry of neonatal cardiomyocytes are mediated by activation of insulin-like growth factor 1 receptor

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Abstract

C-kit-positive neonatal cardiomyocytes (NCMs) contribute to myocardial regeneration. However, the myocardium itself cannot give rise to a robust regenerative response owing to the limited numbers of c-kit-positive resident stem cells present in the heart. It has been shown that mesenchymal stem cells (MSCs) can enhance cardiac repair via the release of paracrine factors such as insulin-like growth factor (IGF-1). We investigated whether the increased expression of c-kit in NCMs mediates the beneficial effects of MSCs on cardiac repair. MSCs and NCMs were prepared from Lewis rats and co-cultured in a Transwell system, which allowed the diffusion of secreted factors but prevented cell contact between the two cell types. The proliferation of NCMs was determined by BrdU assay. The expression of c-kit was assessed by real-time PCR and flow cytometry. The apoptosis rate of NCMs in response to hypoxia was determined by flow cytometry. We found that the expression of c-kit in NCMs was increased by paracrine factors released by MSCs. The effect of paracrine factors on c-kit expression was attenuated by IGF-1 receptor-neutralizing antibody. Furthermore, we found that increased c-kit expression requires IGF-1 receptor activation via the phosphatidylinositol 3 kinase/Akt-mediated pathway. These findings provide a new paradigm for the biological effects of IGF-1 and have significant implications for understanding the beneficial effects of MSCs on myocardial regeneration.

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Acknowledgments

This work was supported by American Heart Association (0765149Y to Y. Li), MacDonald Foundation (07RDM008 to Y. Li), National Institutes of Health (R01HL69509 to Y.J. Geng), and T5 program of Department of Defense (Y.J. Geng), and National Natural Science Foundation of China (30772142, 30571850 to X.Y. Yu).

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Authors and Affiliations

  1. Texas Heart Institute and University of Texas Health Science Center, 6770 Bertner Avenue, Houston, TX, 77030, USA

    Yong-Jian Geng & Yangxin Li

  2. Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, People’s Republic of China

    Xi-Yong Yu, Xiao-Hong Li, Qiu-Xiong Lin, Zhi-Xin Shan & Shu-Guang Lin

  3. Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Yao-Hua Song

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  1. Xi-Yong Yu
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Correspondence to Xi-Yong Yu or Yangxin Li.

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Xi-Yong Yu and Yangxin Li contributed equally to this work.

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Yu, XY., Geng, YJ., Li, XH. et al. The effects of mesenchymal stem cells on c-kit up-regulation and cell-cycle re-entry of neonatal cardiomyocytes are mediated by activation of insulin-like growth factor 1 receptor. Mol Cell Biochem 332, 25–32 (2009). https://doi.org/10.1007/s11010-009-0170-x

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