Skip to main content
SpringerLink
Log in

Herzgewebe aus embryonalen Stammzellen

Heart tissue from embryonic stem cells

  • Leitthema: Forschung mit humanen embryonalen Stammzellen
  • Published:
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz Aims and scope

Zusammenfassung

Embryonale Stammzellen (ES-Zellen) sind Vorläufer aller somatischen Körperzellen und daher als Zellquelle für die Herstellung künstlicher Organsysteme (Tissue Engineering) besonders attraktiv. Dass Zellen grundsätzlich organähnliche Gewebe in der Kulturschale formen können, ist lange bekannt. Die Herstellung künstlicher Herzgewebe gelang zunächst aus Herzmuskelzellen fetaler Hühnchen, neonataler Ratten und Mäuse. Aktuelle Untersuchungen befassen sich vor allem mit der Generierung von Herzgewebe aus Stammzellen. Dabei werden folgende langfristige Ziele verfolgt: (1) Bereitstellung menschlicher Herzgewebe für entwicklungsbiologische Untersuchungen; (2) Herstellung humaner Testsysteme für die pharmakologische und toxikologische Substanz-Entwicklung bzw. -Testung und (3) Entwicklung von Ersatzherzgewebe für eine potenzielle therapeutische Anwendung in vivo. Der vorliegende Übersichtsartikel bespricht zunächst den Hintergrund der Zellbasierten kardialen Regeneration/Reparatur, führt darauf in die unterschiedlichen Konzepte des myokardialen Tissue Engineerings ein, diskutiert die Anwendung embryonaler, aber auch nicht-embryonaler Stammzellen und spekuliert schließlich über das direkte und indirekte therapeutische Potenzial künstlicher Herzgewebe aus menschlichen Stammzellen.

Abstract

Embryonic stem cells can give rise to all somatic cells, making them an attractive cell source for tissue engineering applications. The propensity of cells to form tissue-like structures in a culture dish has been well documented. We and others made use of this intrinsic property to generate bioartificial heart muscle. First proof-of-concept studies involved immature heart cells mainly from fetal chicken, neonatal rats and mice. They eventually provided evidence that force-generating heart muscle can be engineered in vitro. Recently, the focus shifted to the application of stem cells to eventually enable the generation of human heart muscle and reach following long-term goals: (1) development of a simplified in vitro model of heart muscle development; (2) generation of a human test-bed for drug screening and development; (3) allocation of surrogate heart tissue to myocardial repair applications. This overview will provide the background for cell-based myocardial repair, introduce the main myocardial tissue engineering concepts, discuss the use of embryonic and non-embryonic stem cells, and lays out the potential direct and indirect therapeutic use of human tissue engineered myocardium.

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

Literatur

  1. Schannwell CM, Hennersdorf MG, Strauer BE (2007) Hypertension and cardiac failure. Internist (Berl) 48:909–920

    Article  PubMed  CAS  Google Scholar 

  2. Oberpriller JO, Oberpriller J (1974) Response of the adult newt ventricle to injury. J Exp Zool 187:249–253

    Article  PubMed  CAS  Google Scholar 

  3. Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298:2188–2190

    Article  PubMed  CAS  Google Scholar 

  4. Field LJ (1988) Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science 239:1029–1033

    Article  PubMed  CAS  Google Scholar 

  5. Soonpaa MH, Koh GY, Klug MG, Field LJ (1994) Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science 264:98–101

    Article  PubMed  CAS  Google Scholar 

  6. Muller-Ehmsen J, Whittaker P, Kloner RA, et al. (2002) Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J Mol Cell Cardiol 34:107–116

    Article  PubMed  Google Scholar 

  7. Laflamme MA, Chen KY, Naumova AV, et al. (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25:1015–1024

    Article  PubMed  CAS  Google Scholar 

  8. Kofidis T, Lebl DR, Swijnenburg RJ, et al. (2006) Allopurinol/uricase and ibuprofen enhance engraftment of cardiomyocyte-enriched human embryonic stem cells and improve cardiac function following myocardial injury. Eur J Cardiothorac Surg 29:50–55

    Article  PubMed  Google Scholar 

  9. Wobus AM, Wallukat G, Hescheler J (1991) Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers. Differentiation 48:173–182

    Article  PubMed  CAS  Google Scholar 

  10. Doetschman TC, Eistetter H, Katz M, et al. (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 87:27–45

    PubMed  CAS  Google Scholar 

  11. Kehat I, Kenyagin-Karsenti D, Snir M, et al. (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108:407–414

    PubMed  CAS  Google Scholar 

  12. Mummery C, Ward-van Oostwaard D, Doevendans P, et al. (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107:2733–2740

    Article  PubMed  CAS  Google Scholar 

  13. Xu C, Police S, Rao N, Carpenter MK (2002) Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res 91:501–508

    Article  PubMed  CAS  Google Scholar 

  14. Klug MG, Soonpaa MH, Koh GY, Field LJ (1996) Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 98:216–224

    Article  PubMed  CAS  Google Scholar 

  15. Muller M, Fleischmann BK, Selbert S, et al. (2000) Selection of ventricular-like cardiomyocytes from ES cells in vitro. Faseb J 14:2540–2548

    Article  PubMed  CAS  Google Scholar 

  16. Fleischmann M, Bloch W, Kolossov E, et al. (1998) Cardiac specific expression of the green fluorescent protein during early murine embryonic development. FEBS Lett 440:370–376

    Article  PubMed  CAS  Google Scholar 

  17. Zandstra PW, Bauwens C, Yin T, et al. (2003) Scalable production of embryonic stem cell-derived cardiomyocytes. Tissue Eng 9:767–778

    Article  PubMed  CAS  Google Scholar 

  18. Gepstein L (2002) Derivation and potential applications of human embryonic stem cells. Circ Res 91:866–876

    Article  PubMed  CAS  Google Scholar 

  19. Laugwitz KL, Moretti A, Lam J, et al. (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653

    Article  PubMed  CAS  Google Scholar 

  20. David R, Brenner C, Stieber J, et al. (2008) MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol 10:338–435

    Article  PubMed  CAS  Google Scholar 

  21. Moretti A, Caron L, Nakano A, et al. (2006) Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127:1151–1165

    Article  PubMed  CAS  Google Scholar 

  22. Kattman SJ, Huber TL, Keller GM (2006) Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell 11:723–732

    Article  PubMed  CAS  Google Scholar 

  23. Yang L, Soonpaa MH, Adler ED, et al. (2008) Human cardiovascular progenitor cells develop from a KDR(+) embryonic-stem-cell-derived population. Nature 453:524–528

    Article  PubMed  CAS  Google Scholar 

  24. Murry CE, Field LJ, Menasche P (2005) Cell-based cardiac repair: reflections at the 10-year point. Circulation 112:3174–3183

    Article  PubMed  Google Scholar 

  25. Dimmeler S, Zeiher AM, Schneider MD (2005) Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 115:572–583

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Li RK, Yau TM, Weisel RD, et al. (2000) Construction of a bioengineered cardiac graft. J Thorac Cardiovasc Surg 119:368–375

    Article  PubMed  CAS  Google Scholar 

  28. Leor J, Aboulafia-Etzion S, Dar A, et al. (2000) Bioengineered cardiac grafts: a new approach to repair the infarcted myocardium? Circulation 102:III56–61

    PubMed  CAS  Google Scholar 

  29. Langer R, Vacanti JP (1993) Tissue engineering. Science 260:920–926

    Article  PubMed  CAS  Google Scholar 

  30. Bursac N, Papadaki M, Cohen RJ, et al. (1999) Cardiac muscle tissue engineering: toward an in vitro model for electrophysiological studies. Am J Physiol 277:H433–H444

    PubMed  CAS  Google Scholar 

  31. Carrier RL, Papadaki M, Rupnick M, et al. (1999) Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue construct characterization. Biotechnol Bioeng 64:580–589

    Article  PubMed  CAS  Google Scholar 

  32. Caspi O, Lesman A, Basevitch Y, et al. (2007) Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ Res 100:263–272

    Article  PubMed  CAS  Google Scholar 

  33. Radisic M, Park H, Shing H, et al. (2004) Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc Natl Acad Sci USA 101:18129–18134

    Article  PubMed  CAS  Google Scholar 

  34. Ott HC, Matthiesen TS, Goh SK, et al. (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14:213–221

    Article  PubMed  CAS  Google Scholar 

  35. Eschenhagen T, Fink C, Remmers U, et al. (1997) Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. Faseb J 11:683–694

    PubMed  CAS  Google Scholar 

  36. Zimmermann WH, Fink C, Kralisch D, et al. (2000) Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. Biotechnol Bioeng 68:106–114

    Article  PubMed  CAS  Google Scholar 

  37. Zimmermann WH, Schneiderbanger K, Schubert P, et al. (2002) Tissue engineering of a differentiated cardiac muscle construct. Circ Res 90:223–230

    Article  PubMed  CAS  Google Scholar 

  38. Fink C, Ergun S, Kralisch D, et al. (2000) Chronic stretch of engineered heart tissue induces hypertrophy and functional improvement. Faseb J 14:669–679

    PubMed  CAS  Google Scholar 

  39. Shimizu T, Yamato M, Isoi Y, et al. (2002) Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensional cell sheet manipulation technique and temperature-responsive cell culture surfaces. Circ Res 90:e40

    Article  PubMed  CAS  Google Scholar 

  40. Shimizu T, Sekine H, Yang J, et al. (2006) Polysurgery of cell sheet grafts overcomes diffusion limits to produce thick, vascularized myocardial tissues. Faseb J 20:708–710

    PubMed  CAS  Google Scholar 

  41. Eschenhagen T, Zimmermann WH (2005) Engineering myocardial tissue. Circ Res 97:1220–1231

    Article  PubMed  CAS  Google Scholar 

  42. Zimmermann WH, Didie M, Doker S, et al. (2006) Heart muscle engineering: an update on cardiac muscle replacement therapy. Cardiovasc Res 71:419–429

    Article  PubMed  CAS  Google Scholar 

  43. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  PubMed  CAS  Google Scholar 

  44. Reyes M, Lund T, Lenvik T, et al. (2001) Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98:2615–2625

    Article  PubMed  CAS  Google Scholar 

  45. Pittenger MF, Mackay AM, Beck SC, et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  PubMed  CAS  Google Scholar 

  46. Badorff C, Brandes RP, Popp R, et al. (2003) Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 107:1024–1032

    Article  PubMed  Google Scholar 

  47. Orlic D, Kajstura J, Chimenti S, et al. (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705

    Article  PubMed  CAS  Google Scholar 

  48. Jackson KA, Majka SM, Wang H, et al. (2001) Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107:1395–1402

    Article  PubMed  CAS  Google Scholar 

  49. Goumans MJ, de Boer TP, Smits AM, et al. (2008) TGF-β1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res (in press)

  50. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  PubMed  CAS  Google Scholar 

  51. Guan K, Nayernia K, Maier LS, et al. (2006) Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440:1199–1203

    Article  PubMed  CAS  Google Scholar 

  52. Vrana KE, Hipp JD, Goss AM, et al. (2003) Nonhuman primate parthenogenetic stem cells. Proc Natl Acad Sci USA 100(Suppl 1):11911–11916

    Article  PubMed  CAS  Google Scholar 

  53. Stewart S, MacIntyre K, Hole DJ, et al. (2001) More „malignant“ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 3:315–322

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Universitätsklinikum Hamburg-Eppendorf, Hamburg, BRD

    Wolfram-Hubertus Zimmermann

  2. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, BRD

    Wolfram-Hubertus Zimmermann

Authors
  1. Wolfram-Hubertus Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfram-Hubertus Zimmermann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zimmermann, WH. Herzgewebe aus embryonalen Stammzellen. Bundesgesundheitsbl. 51, 1021–1025 (2008). https://doi.org/10.1007/s00103-008-0630-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00103-008-0630-6

Schlüsselwörter

Keywords

Search

Navigation