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Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts

Abstract

The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1–4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

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Figure 1: Construction of optimized EHTs. Effects of oxygen, load and insulin were analyzed by isometric contraction experiments in EHT rings.
Figure 2: EHT morphology 4 weeks after engraftment.
Figure 3: Electrical integration of EHTs in vivo.
Figure 4: Changes in left ventricular function after EHT implantation.
Figure 5: Influence of EHT grafting on left ventricular hemodynamics.

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References

  1. Murry, C.E., Field, L.J. & Menasche, P. Cell-based cardiac repair: reflections at the 10-year point. Circulation 112, 3174–3183 (2005).

    Article  Google Scholar 

  2. Eschenhagen, T. & Zimmermann, W.H. Engineering myocardial tissue. Circ. Res. 97, 1220–1231 (2005).

    Article  CAS  Google Scholar 

  3. Reinecke, H., Zhang, M., Bartosek, T. & Murry, C.E. Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. Circulation 100, 193–202 (1999).

    Article  CAS  Google Scholar 

  4. Condorelli, G. et al. Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc. Natl. Acad. Sci. USA 98, 10733–10738 (2001).

    Article  CAS  Google Scholar 

  5. Muller-Ehmsen, J. et al. Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation 105, 1720–1726 (2002).

    Article  Google Scholar 

  6. Li, R.K. et al. Natural history of fetal rat cardiomyocytes transplanted into adult rat myocardial scar tissue. Circulation 96 Suppl., II-179–86; discussion 186–7 (1997).

    Google Scholar 

  7. Taylor, D.A. et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat. Med. 4, 929–933 (1998).

    Article  CAS  Google Scholar 

  8. Soonpaa, M.H., Koh, G.Y., Klug, M.G. & Field, L.J. Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science 264, 98–101 (1994).

    Article  CAS  Google Scholar 

  9. Assmus, B. et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106, 3009–3017 (2002).

    Article  Google Scholar 

  10. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    Article  CAS  Google Scholar 

  11. Stamm, C. et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361, 45–46 (2003).

    Article  Google Scholar 

  12. Strauer, B.E. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106, 1913–1918 (2002).

    Article  Google Scholar 

  13. Beltrami, A.P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).

    Article  CAS  Google Scholar 

  14. Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. USA 100, 12313–12318 (2003).

    Article  CAS  Google Scholar 

  15. Balsam, L.B. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673 (2004).

    Article  CAS  Google Scholar 

  16. Murry, C.E. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004).

    Article  CAS  Google Scholar 

  17. Nygren, J.M. et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat. Med. 10, 494–501 (2004).

    Article  CAS  Google Scholar 

  18. Kehat, I. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest. 108, 407–414 (2001).

    Article  CAS  Google Scholar 

  19. Laugwitz, K.L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).

    Article  CAS  Google Scholar 

  20. Messina, E. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004).

    Article  CAS  Google Scholar 

  21. Eschenhagen, T. et al. Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. FASEB J. 11, 683–694 (1997).

    Article  CAS  Google Scholar 

  22. Zimmermann, W.H. et al. Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. Biotechnol. Bioeng. 68, 106–114 (2000).

    Article  CAS  Google Scholar 

  23. Zimmermann, W.H. et al. Tissue engineering of a differentiated cardiac muscle construct. Circ. Res. 90, 223–230 (2002).

    Article  CAS  Google Scholar 

  24. Carrier, R.L. et al. Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue construct characterization. Biotechnol. Bioeng. 64, 580–589 (1999).

    Article  CAS  Google Scholar 

  25. Leor, J. et al. Bioengineered cardiac grafts: A new approach to repair the infarcted myocardium? Circulation 102 Suppl. 3, III56–III61 (2000).

    CAS  PubMed  Google Scholar 

  26. Li, R.K. et al. Survival and function of bioengineered cardiac grafts. Circulation 100 Suppl., II63–II69 (1999).

    CAS  PubMed  Google Scholar 

  27. Zimmermann, W.H. et al. Cardiac grafting of engineered heart tissue in syngenic rats. Circulation 106, I151–I157 (2002).

    PubMed  Google Scholar 

  28. Dhein, S., Muller, A., Gerwin, R. & Klaus, W. Comparative study on the proarrhythmic effects of some antiarrhythmic agents. Circulation 87, 617–630 (1993).

    Article  CAS  Google Scholar 

  29. Menasche, P. et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J. Am. Coll. Cardiol. 41, 1078–1083 (2003).

    Article  Google Scholar 

  30. Jackson, K.A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

This work is part of the doctoral thesis of I.M. at the Universities of Erlangen-Nuremberg and Hamburg. We acknowledge the technical assistance of S. John and F. Bussmann (University of Erlangen; MRI data evaluation) and T. Müller (University of Erlangen; construction of stretch devices). The help from H. Rütten and D. Gehling (Aventis, Frankfurt) in echocardiography and pressure-volume loop recordings is appreciated. This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Es 88/8-2 to T.E. and FOR 604/1-1 to T.E. and H.E.), the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung 01GN 0124 and BMBF 01GN 0520 to T.E. and W.-H.Z.), the Deutsche Stiftung für Herzforschung (W.-H.Z.) and the Minerva foundation (W.-H.Z.).

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Correspondence to Wolfram-Hubertus Zimmermann or Thomas Eschenhagen.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Relating functional effects of optimized EHTs to molecular alterations in EHTs. (PDF 115 kb)

Supplementary Fig. 2

Cell composition of multi-unit EHTs. (PDF 114 kb)

Supplementary Fig. 3

Echocardiography assessment. (PDF 398 kb)

Supplementary Fig. 4

DAPI labeling of EHT grafts. (PDF 17896 kb)

Supplementary Fig. 5

Ambulatory echocardiogram telemetry. (PDF 101 kb)

Supplementary Table 1

Summary of the experimental outline. (PDF 23 kb)

Supplementary Table 2

Echocardiography data. (PDF 267 kb)

Supplementary Table 3

MRI data. (PDF 115 kb)

Supplementary Table 4

Catheterization data. (PDF 151 kb)

Supplementary Video 1

Multiunit engineered heart tissue. (MOV 6008 kb)

Supplementary Methods (PDF 47 kb)

Supplementary Note (PDF 59 kb)

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Zimmermann, WH., Melnychenko, I., Wasmeier, G. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 12, 452–458 (2006). https://doi.org/10.1038/nm1394

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