Skip to main content
SpringerLink
Log in

Transplantation of iPSc Restores Cardiac Function by Promoting Angiogenesis and Ameliorating Cardiac Remodeling in a Post-infarcted Swine Model

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Induced pluripotent stem cells (iPSc) hold significant promise for the development of cardiac regenerative therapy for myocardial infarction (MI). However, preclinical optimization and validation of large-animal models will be required before iPSc used clinically. Therefore, we aim to investigate the therapeutic potential of iPSc transplantation for MI and relative mechanisms in a post-infarcted swine model. Left anterior descending coronary artery was balloon-occluded after percutaneous transluminal angiography to generate MI (60-min no-flow ischemia). Animals were then divided into Sham, PBS control, and iPS experimental groups. The cardiac function and LV structural were assessed by dual-source computed tomography. Terminal deoxynucleotidyl nick end labeling, histology, and immunofluorescence were used to examine the effect of transplanted iPS cells on apoptosis, fibrosis, and hypertrophy. At 6 weeks, LV structural abnormality and cardiac dysfunction were less pronounced in iPSc group than in PBS group, and these improvements were accompanied by reduction of scar size. iPSc transplantation was associated with significant increase of vascular density and reduced myocardial apoptosis in the border zone of infarction, which was accompanied by the reduction in fibrosis degree. Moreover, proangiogenic and antiapoptotic factors were increased significantly in iPS group compared with PBS group. Cardiomyocyte hypertrophy was significantly attenuated by iPSc transplantation. In conclusion, these results suggested that transplantation of iPSc may result in functional recovery by promoting angiogenesis, inhibiting apoptosis, and ameliorating cardiac remodeling. This proof of concept study may provide a basis for an autologous iPSc-based therapy of MI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Quijada, P., Toko, H., Fischer, K. M., Bailey, B., Reilly, P., Hunt, K. D., et al. (2012). Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells. Circulation Research, 111, 77–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Takemura, G., & Fujiwara, H. (2004). Role of apoptosis in remodeling after myocardial infarction. Pharmacology and Therapeutics, 104, 1–16.

    Article  CAS  PubMed  Google Scholar 

  3. Pfeffer, M. A., & Braunwald, E. (1990). Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation, 81, 1161–1172.

    Article  CAS  PubMed  Google Scholar 

  4. Foo, R. S., Mani, K., & Kitsis, R. N. (2005). Death begets failure in the heart. Journal of Clinical Investigation, 115, 565–571.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Yamanaka, S. (2007). Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell, 1, 39–49.

    Article  CAS  PubMed  Google Scholar 

  6. Nishikawa, S., Goldstein, R. A., & Nierras, C. R. (2008). The promise of human induced pluripotent stem cells for research and therapy. Nature Reviews Molecular Cell Biology, 9, 725–729.

    Article  CAS  PubMed  Google Scholar 

  7. Haase, A., Olmer, R., Schwanke, K., Wunderlich, S., Merkert, S., Hess, C., et al. (2009). Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell, 5, 434–441.

    Article  CAS  PubMed  Google Scholar 

  8. Mauritz, C., Schwanke, K., Reppel, M., Neef, S., Katsirntaki, K., Maier, L. S., et al. (2008). Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation, 118, 507–517.

    Article  PubMed  Google Scholar 

  9. Narazaki, G., Uosaki, H., Teranishi, M., Okita, K., Kim, B., Matsuoka, S., et al. (2008). Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation, 118, 498–506.

    Article  PubMed  Google Scholar 

  10. Schenke-Layland, K., Rhodes, K. E., Angelis, E., Butylkova, Y., Heydarkhan-Hagvall, S., Gekas, C., et al. (2008). Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Stem Cells, 26, 1537–1546.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Olmer, R., Haase, A., Merkert, S., Cui, W., Palecek, J., Ran, C., et al. (2010). Long term expansion of undifferentiated human iPS and ES cells in suspension culture using a defined medium. Stem Cell Research, 5, 51–64.

    Article  CAS  PubMed  Google Scholar 

  12. Zweigerdt, R., Olmer, R., Singh, H., Haverich, A., & Martin, U. (2011). Scalable expansion of human pluripotent stem cells in suspension culture. Nature Protocols, 6, 689–700.

    Article  CAS  PubMed  Google Scholar 

  13. Singla, D. K., Long, X., Glass, C., Singla, R. D., & Yan, B. (2011). Induced pluripotent stem (iPS) cells repair and regenerate infarcted myocardium. Molecular Pharmaceutics, 8, 1573–1581.

    Article  CAS  PubMed  Google Scholar 

  14. Mauritz, C., Martens, A., Rojas, S. V., Schnick, T., Rathert, C., Schecker, N., et al. (2011). Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. European Heart Journal, 32, 2634–2641.

    Article  CAS  PubMed  Google Scholar 

  15. Nelson, T. J., Martinez-Fernandez, A., Yamada, S., Perez-Terzic, C., Ikeda, Y., & Terzic, A. (2009). Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation, 120, 408–416.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Wu, Z., Chen, J., Ren, J., Bao, L., Liao, J., Cui, C., et al. (2009). Generation of pig induced pluripotent stem cells with a drug-inducible system. Journal of Molecular Cell Biology, 1, 46–54.

    Article  CAS  PubMed  Google Scholar 

  17. Yang, Y. J., Qian, H. Y., Huang, J., Li, J. J., Gao, R. L., Dou, K. F., et al. (2009). Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 2076–2082.

    Article  PubMed  Google Scholar 

  18. Li, C., Tang, L., Yang, Z., & Cao, K. (2011). Integration of dual source computed tomography with magnetic navigation system for percutaneous coronary intervention: a feasibility study. Catheterization and Cardiovascular Interventions, 78, 1108–1115.

    Article  PubMed  Google Scholar 

  19. Zhang, S., Ge, J., Zhao, L., Qian, J., Huang, Z., Shen, L., et al. (2007). Host vascular niche contributes to myocardial repair induced by intracoronary transplantation of bone marrow CD34+ progenitor cells in infarcted swine heart. Stem Cells, 25, 1195–1203.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, Z., Li, S., Cui, M., Gao, X., Sun, D., Qin, X., et al. (2013). Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3 K/Akt and MEK/ERK pathways. Basic Research in Cardiology, 108, 333.

    Article  PubMed  Google Scholar 

  21. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917–1920.

    Article  CAS  PubMed  Google Scholar 

  22. Menasche, P. (2004). Cellular transplantation: hurdles remaining before widespread clinical use. Current Opinion in Cardiology, 19, 154–161.

    Article  PubMed  Google Scholar 

  23. Amado, L. C., Saliaris, A. P., Schuleri, K. H., St John, M., Xie, J. S., Cattaneo, S., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the USA, 102, 11474–11479.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Yan, B., Abdelli, L. S., & Singla, D. K. (2011). Transplanted induced pluripotent stem cells improve cardiac function and induce neovascularization in the infarcted hearts of db/db mice. Molecular Pharmaceutics, 8, 1602–1610.

    Article  CAS  PubMed  Google Scholar 

  25. Bolognese, L., Neskovic, A. N., Parodi, G., Cerisano, G., Buonamici, P., Santoro, G. M., et al. (2002). Left ventricular remodeling after primary coronary angioplasty: Patterns of left ventricular dilation and long-term prognostic implications. Circulation, 106, 2351–2357.

    Article  PubMed  Google Scholar 

  26. Hu, Q., Wang, X., Lee, J., Mansoor, A., Liu, J., Zeng, L., et al. (2006). Profound bioenergetic abnormalities in peri-infarct myocardial regions. American Journal of Physiology Heart and Circulatory Physiology, 291, 648–657.

    Article  Google Scholar 

  27. Kumar, D., & Jugdutt, B. I. (2003). Apoptosis and oxidants in the heart. Journal of Laboratory and Clinical Medicine, 142, 288–297.

    Article  CAS  PubMed  Google Scholar 

  28. Kumar, D., Lou, H., & Singal, P. K. (2002). Oxidative stress and apoptosis in heart dysfunction. Herz, 27, 662–668.

    Article  PubMed  Google Scholar 

  29. Jugdutt, B. I. (2003). Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Current Drug Targets: Cardiovascular and Haematological Disorders, 3, 1–30.

    CAS  PubMed  Google Scholar 

  30. Jugdutt, B. I. (2003). Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough. Circulation, 108, 1395–1403.

    Article  PubMed  Google Scholar 

  31. Jugdutt, B. I., Menon, V., Kumar, D., & Idikio, H. (2002). Vascular remodeling during healing after myocardial infarction in the dog model: Effects of reperfusion, amlodipine and enalapril. Journal of the American College of Cardiology, 39, 1538–1545.

    Article  PubMed  Google Scholar 

  32. Fatma, S., Selby, D. E., Singla, R. D., & Singla, D. K. (2010). Factors Released from Embryonic Stem Cells Stimulate c-kit-FLK-1(+ve) Progenitor Cells and Enhance Neovascularization. Antioxidants and Redox Signaling, 13, 1857–1865.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Singla, D. K., Lyons, G. E., & Kamp, T. J. (2007). Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling. American Journal of Physiology Heart and Circulatory Physiology, 293, 1308–1314.

    Article  Google Scholar 

  34. Xiong, Q., Ye, L., Zhang, P., Lepley, M., Swingen, C., Zhang, L., et al. (2012). Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells. Circulation Research, 111, 455–468.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81170160, 30871077, 30800464).

Author information

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Guixian Song, Xiaorong Li, Lingmei Qian, Xiangqing Kong, Minglong Chen, Kejiang Cao & Fengxiang Zhang

  2. State Key Laboratory of Reproductive Medicine, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, China

    Yahui Shen

Authors
  1. Guixian Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaorong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yahui Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lingmei Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiangqing Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minglong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kejiang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fengxiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kejiang Cao or Fengxiang Zhang.

Additional information

Guixian Song, Xiaorong Li and Yahui Shen have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, G., Li, X., Shen, Y. et al. Transplantation of iPSc Restores Cardiac Function by Promoting Angiogenesis and Ameliorating Cardiac Remodeling in a Post-infarcted Swine Model. Cell Biochem Biophys 71, 1463–1473 (2015). https://doi.org/10.1007/s12013-014-0369-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-014-0369-7

Keywords

Search

Navigation