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

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.

[1]  D. Torella,et al.  Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration , 2003, Cell.

[2]  C. Murry,et al.  Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. , 1999, Circulation.

[3]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[4]  Thomas Eschenhagen,et al.  Three‐dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[6]  Bernd Westphal,et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration , 2003, The Lancet.

[7]  Michael D. Schneider,et al.  Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Peter W. Laird,et al.  Rebuilding a Damaged Heart: Long-Term Survival of Transplanted Neonatal Rat Cardiomyocytes After Myocardial Infarction and Effect on Cardiac Function , 2002, Circulation.

[9]  G. Koh,et al.  Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. , 1994, Science.

[10]  A. Hagège,et al.  Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. , 2003, Journal of the American College of Cardiology.

[11]  I. Weissman,et al.  Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium , 2004, Nature.

[12]  Doris A Taylor,et al.  Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation , 1998, Nature Medicine.

[13]  G. Cossu,et al.  Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium regeneration , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  W. Zimmermann,et al.  Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. , 2000, Biotechnology and bioengineering.

[15]  Giulio Cossu,et al.  Isolation and Expansion of Adult Cardiac Stem Cells From Human and Murine Heart , 2004, Circulation research.

[16]  Thomas Eschenhagen,et al.  Engineering Myocardial Tissue , 2005, Circulation research.

[17]  Karl-Ludwig Laugwitz,et al.  Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages , 2005, Nature.

[18]  P. Menasché,et al.  Cell-based cardiac repair: reflections at the 10-year point. , 2005, Circulation.

[19]  M. Entman,et al.  Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. , 2001, The Journal of clinical investigation.

[20]  Andreas Hess,et al.  Cardiac Grafting of Engineered Heart Tissue in Syngenic Rats , 2002, Circulation.

[21]  B. Fleischmann,et al.  Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation , 2004, Nature Medicine.

[22]  R. Weisel,et al.  Survival and function of bioengineered cardiac grafts. , 1999, Circulation.

[23]  W. Klaus,et al.  Comparative Study on the Proarrhythmic Effects of Some Antiarrhythmic Agents , 1993, Circulation.

[24]  J. Leor,et al.  Bioengineered Cardiac Grafts: A New Approach to Repair the Infarcted Myocardium? , 2000, Circulation.

[25]  W. Zimmermann,et al.  Tissue Engineering of a Differentiated Cardiac Muscle Construct , 2002, Circulation research.

[26]  F J Schoen,et al.  Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue construct characterization. , 1999, Biotechnology and bioengineering.

[27]  L Gepstein,et al.  Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. , 2001, The Journal of clinical investigation.

[28]  P. Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002, Circulation.

[29]  David A. Williams,et al.  Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts , 2004, Nature.

[30]  R. Weisel,et al.  Natural history of fetal rat cardiomyocytes transplanted into adult rat myocardial scar tissue. , 1997, Circulation.