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Circulation. 2017 May 9;135(19):1832-1847. doi: 10.1161/CIRCULATIONAHA.116.024145. Epub 2017 Feb 6.

Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair.

Author information

1
From Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Germany (M.T., J.E.H., P.B., S.S., T.M., M.-L.C.L., E.L., F.R., S.Z., E. Wettwer, W.-H.Z.); German Center for Cardiovascular Research (DZHK), partner site Göttingen, Germany (M.T., J.E.H., P.B., S.S., T.M., M.-L.C.L., E.L., F.R., S.Z., E. Wingender, W.A.L., W.-H.Z.); Institute of Bioinformatics, University Medical Center Göttingen, Germany (S.Z., E. Wingender); Stanford Cardiovascular Institute (J.R., M.W., J.D.G., J.C.W.) and Department of Radiology (J.D.G., J.C.W.), Molecular Imaging Program, Stanford University School of Medicine, CA; The Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology, Haifa (I.K., L.G.); Institute of Pharmacology and Toxicology, Technical University Dresden, Germany (E. Wettwer, U.R.); University Medical Center Utrecht and Hubrecht Institute, The Netherlands (P.D., L.W.v.L.); Leiden University Medical Center, The Netherlands (M.J.G.); Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Germany (S.K., K.T., G.H., W.A.L.); Center for Applied Technology, Beckman Research Institute, City of Hope, Duarte, CA (L.A.C.); Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany (A.U., W.A.L.); New Laura and Isaac Perlmutter Cancer Center at New York University Langone (T.A., B.N.); and McEwen Centre for Regenerative Medicine, Toronto, Canada (G.K.). The current address for Dr Hudson is Laboratory for Cardiac Regeneration, School of Biomedical Sciences, The University of Queensland, Australia.
2
From Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Germany (M.T., J.E.H., P.B., S.S., T.M., M.-L.C.L., E.L., F.R., S.Z., E. Wettwer, W.-H.Z.); German Center for Cardiovascular Research (DZHK), partner site Göttingen, Germany (M.T., J.E.H., P.B., S.S., T.M., M.-L.C.L., E.L., F.R., S.Z., E. Wingender, W.A.L., W.-H.Z.); Institute of Bioinformatics, University Medical Center Göttingen, Germany (S.Z., E. Wingender); Stanford Cardiovascular Institute (J.R., M.W., J.D.G., J.C.W.) and Department of Radiology (J.D.G., J.C.W.), Molecular Imaging Program, Stanford University School of Medicine, CA; The Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology, Haifa (I.K., L.G.); Institute of Pharmacology and Toxicology, Technical University Dresden, Germany (E. Wettwer, U.R.); University Medical Center Utrecht and Hubrecht Institute, The Netherlands (P.D., L.W.v.L.); Leiden University Medical Center, The Netherlands (M.J.G.); Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Germany (S.K., K.T., G.H., W.A.L.); Center for Applied Technology, Beckman Research Institute, City of Hope, Duarte, CA (L.A.C.); Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany (A.U., W.A.L.); New Laura and Isaac Perlmutter Cancer Center at New York University Langone (T.A., B.N.); and McEwen Centre for Regenerative Medicine, Toronto, Canada (G.K.). The current address for Dr Hudson is Laboratory for Cardiac Regeneration, School of Biomedical Sciences, The University of Queensland, Australia. w.zimmermann@med.uni-goettingen.de.

Abstract

BACKGROUND:

Advancing structural and functional maturation of stem cell-derived cardiomyocytes remains a key challenge for applications in disease modeling, drug screening, and heart repair. Here, we sought to advance cardiomyocyte maturation in engineered human myocardium (EHM) toward an adult phenotype under defined conditions.

METHODS:

We systematically investigated cell composition, matrix, and media conditions to generate EHM from embryonic and induced pluripotent stem cell-derived cardiomyocytes and fibroblasts with organotypic functionality under serum-free conditions. We used morphological, functional, and transcriptome analyses to benchmark maturation of EHM.

RESULTS:

EHM demonstrated important structural and functional properties of postnatal myocardium, including: (1) rod-shaped cardiomyocytes with M bands assembled as a functional syncytium; (2) systolic twitch forces at a similar level as observed in bona fide postnatal myocardium; (3) a positive force-frequency response; (4) inotropic responses to β-adrenergic stimulation mediated via canonical β1- and β2-adrenoceptor signaling pathways; and (5) evidence for advanced molecular maturation by transcriptome profiling. EHM responded to chronic catecholamine toxicity with contractile dysfunction, cardiomyocyte hypertrophy, cardiomyocyte death, and N-terminal pro B-type natriuretic peptide release; all are classical hallmarks of heart failure. In addition, we demonstrate the scalability of EHM according to anticipated clinical demands for cardiac repair.

CONCLUSIONS:

We provide proof-of-concept for a universally applicable technology for the engineering of macroscale human myocardium for disease modeling and heart repair from embryonic and induced pluripotent stem cell-derived cardiomyocytes under defined, serum-free conditions.

KEYWORDS:

heart failure; models, cardiovascular; regeneration; stem cells; tissue engineering

PMID:
28167635
PMCID:
PMC5501412
DOI:
10.1161/CIRCULATIONAHA.116.024145
[Indexed for MEDLINE]
Free PMC Article

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