期刊
CIRCULATION
卷 135, 期 19, 页码 1832-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.116.024145
关键词
heart failure; models, cardiovascular; regeneration; stem cells; tissue engineering
资金
- DZHK (German Center for Cardiovascular Research)
- German Federal Ministry for Science and Education [BMBF FKZ 13GW0007A [CIRM-ET3]]
- German Research Foundation (DFG) [ZI 708/7-1, ZI 708/8-1, ZI 708/10-1, SFB 937 TP18, SFB 1002 TPs B03, C04, S1, IRTG 1618]
- Lower Saxony-Israel grant [11-76251-99-30/09]
- European Union FP7 CARE-MI
- Foundation Leducq
- National Institutes of Health [U01 HL099997]
- California Institute of Regenerative Medicine [CIRM DR2A-05394, CIRM TR3-05556, CIRM RT3-07798]
- NIRM (Netherlands Institute for Regenerative Medicine)
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 beta-adrenergic stimulation mediated via canonical beta(1)- and beta(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.
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