TY - JOUR
T1 - Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair
AU - Tiburcy, Malte
AU - Hudson, James E.
AU - Balfanz, Paul
AU - Schlick, Susanne
AU - Meyer, Tim
AU - Liao, Mei Ling Chang
AU - Levent, Elif
AU - Raad, Farah
AU - Zeidler, Sebastian
AU - Wingender, Edgar
AU - Riegler, Johannes
AU - Wang, Mouer
AU - Gold, Joseph D.
AU - Kehat, Izhak
AU - Wettwer, Erich
AU - Ravens, Ursula
AU - Dierickx, Pieterjan
AU - Van Laake, Linda W.
AU - Goumans, Marie-Jose
AU - Khadjeh, Sara
AU - Toischer, Karl
AU - Hasenfuss, Gerd
AU - Couture, Larry A.
AU - Unger, Andreas
AU - Linke, Wolfgang A.
AU - Araki, Toshiyuki
AU - Neel, Benjamin
AU - Keller, Gordon
AU - Gepstein, Lior
AU - Wu, Joseph C.
AU - Zimmermann, Wolfram-Hubertus
N1 - Funding Information:
This study was supported by DZHK (German Center for Cardiovascular Research), the German Federal Ministry for Science and Education (BMBF FKZ 13GW0007A [CIRM-ET3]), the German Research Foundation (DFG ZI 708/7-1, 8-1, 10-1; SFB 937 TP18, SFB 1002 TPs B03, C04, S1; IRTG 1618), a Lower Saxony-Israel grant (11-76251-99-30/09), the European Union FP7 CARE-MI, the Foundation Leducq, and the National Institutes of Health (U01 HL099997). This study was also supported by the California Institute of Regenerative Medicine (CIRM DR2A-05394, CIRM TR3-05556, and CIRM RT3-07798). The collection and studies of fetal material is partly funded by NIRM (Netherlands Institute for Regenerative Medicine).
Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/5/9
Y1 - 2017/5/9
N2 - 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 β 1 - and β 2 -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.
AB - 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 β 1 - and β 2 -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.
KW - heart failure
KW - models, cardiovascular
KW - regeneration
KW - stem cells
KW - tissue engineering
UR - http://www.scopus.com/inward/record.url?scp=85016075727&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.116.024145
DO - 10.1161/CIRCULATIONAHA.116.024145
M3 - Article
C2 - 28167635
AN - SCOPUS:85016075727
SN - 0009-7322
VL - 135
SP - 1832
EP - 1847
JO - Circulation
JF - Circulation
IS - 19
ER -