Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells.
Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell-derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart.
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Florian
F
Weinberger
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Kaja
K
Breckwoldt
German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.|Department of Cardiovascular Surgery, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Simon
S
Pecha
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7030 Trondheim, Norway.|Norwegian Council on Cardiovascular Disease, Oslo, Norway.
Allen
A
Kelly
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Birgit
B
Geertz
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Jutta
J
Starbatty
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Timur
T
Yorgan
Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Boston, MA 02114, USA.
Kai-Hung
KH
Cheng
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Katrin
K
Lessmann
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7030 Trondheim, Norway.|Norwegian Council on Cardiovascular Disease, Oslo, Norway.
Tomas
T
Stolen
Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Boston, MA 02114, USA.
Marielle
M
Scherrer-Crosbie
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7030 Trondheim, Norway.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
Godfrey
G
Smith
German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.|Department of Cardiovascular Surgery, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Hermann
H
Reichenspurner
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Arne
A
Hansen
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. t.eschenhagen@uke.de.|German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
Thomas
T
Eschenhagen
D000818:Animals; D006348:Cardiac Surgical Procedures; D002454:Cell Differentiation; D049109:Cell Proliferation; D002921:Cicatrix; D004452:Echocardiography; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008168:Lung / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation; D012038:Regeneration; D013154:Spleen / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*