Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation

被引:268
|
作者
Hirt, Marc N. [1 ,2 ]
Boeddinghaus, Jasper [1 ,2 ]
Mitchell, Alice [3 ]
Schaaf, Sebastian [1 ]
Boernchen, Christian [4 ]
Mueller, Christian [2 ,5 ]
Schulz, Herbert [6 ,7 ]
Hubner, Norbert [6 ,7 ]
Stenzig, Justus [1 ,2 ]
Stoehr, Andrea [1 ]
Neuber, Christiane [1 ,2 ]
Eder, Alexandra [1 ,2 ]
Luther, Pradeep K. [3 ]
Hansen, Arne [1 ,2 ]
Eschenhagen, Thomas [1 ,2 ]
机构
[1] Univ Med Ctr Hamburg Eppendorf, Dept Expt Pharmacol & Toxicol, D-20246 Hamburg, Germany
[2] DZHK German Ctr Cardiovasc Res, Lubeck, Germany
[3] Univ London Imperial Coll Sci Technol & Med, Fac Med, Natl Heart & Lung Inst, London SW7 2AZ, England
[4] Univ Med Ctr Hamburg Eppendorf, Dermatol & Venereol Dept & Clin, D-20246 Hamburg, Germany
[5] Univ Med Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany
[6] Max Delbruck Ctr Mol Med MDC, Berlin, Germany
[7] DZHK German Ctr Cardiovasc Res, Berlin, Germany
关键词
Electrical stimulation; Cardiac tissue engineering; Cardiomyocyte maturation; Induced pluripotent stem cells; Cardiomyocytes; 2-photon microscopy; CARDIAC MYOCYTES; GROWTH; MYOCARDIUM; PLATFORM; MODELS; FORCE; CA2+;
D O I
10.1016/j.yjmcc.2014.05.009
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Spontaneously beating engineered heart tissue (EHT) represents an advanced in vitro model for drug testing and disease modeling, but cardiomyocytes in EHTs are less mature and generate lower forces than in the adult heart. We devised a novel pacing system integrated in a setup for videooptical recording of EHT contractile function over time and investigated whether sustained electrical field stimulation improved EHT properties. EHTs were generated from neonatal rat heart cells (rEHT, n = 96) or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hEHT, n = 19). Pacing with biphasic pulses was initiated on day 4 of culture. REHT continuously paced for 16-18 days at 0.5 Hz developed 2.2x higher forces than nonstimulated rEHT. This was reflected by higher cardiomyocyte density in the center of EHTs, increased connexin-43 abundance as investigated by two-photon microscopy and remarkably improved sarcomere ultrastructure including regular M-bands. Further signs of tissue maturation include a rightward shift (to more physiological values) of the Ca2+-response curve, increased force response to isoprenaline and decreased spontaneous beating activity. Human EHTs stimulated at 2 Hz in the first week and 1.5 Hz thereafter developed 1.5 x higher forces than nonstimulated hEHT on day 14, an ameliorated muscular network of longitudinally oriented cardiomyocytes and a higher cytoplasm-tonucleus ratio. Taken together, continuous pacing improved structural and functional properties of rEHTs and hEHTs to an unprecedented level. Electrical stimulation appears to be an important step toward the generation of fully mature EHT. (C) 2014 The Authors. Published by Elsevier Ltd.
引用
收藏
页码:151 / 161
页数:11
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