Engineered heart tissue: high throughput platform for dissection of complex diseases.
ABSTRACT The polygenic nature of resistance/sensitivity of the heart to ischemia is generally accepted. Unfortunately, little is known about gene(s) involved in response to this insult. The goal of present study is to introduce new tool, engineered heart tissue (EHT), for accelerating positional cloning and for providing novel functional assays.
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ABSTRACT: According to the Frank-Starling mechanism, as the heart is stretched, it increases its contraction force. Reconstitution of the Frank-Starling mechanism is an important milestone for producing functional heart tissue constructs. Spontaneously contracting engineered heart tissues (EHTs) were reconstituted by growing dissociated chicken embryo cardiomyocytes in collagen matrices. Twitch and baseline tensions were recorded at precisely controlled levels of tissue strain. The EHTs showed a steep increase in twitch tension from 0.47 +/- 0.02 to 0.91 +/- 0.02 mN/mm2 as they were stretched at a constant rate (2.67% per min) from 86% to 100% of the length at which maximum twitch force was exerted. In response to a sudden stretch (3.3%), the twitch tension increased gradually (approximately 60 s) in a Gd3+-sensitive manner, suggesting the presence of stretch-activated Ca2+ channels. A large difference in baseline tension between lengthening (loading) and shortening (unloading) was also recorded. Disruption of nonsarcomeric actin filaments by cytochalasin D and latrunculin B decreased this difference. A simple mechanical model interprets these results in terms of mechanical connections between myocytes and nonmuscle cells. The experimental results strongly suggest that regulation of twitch tension in EHTs is similar to that of natural myocardium.Biophysical Journal 10/2006; 91(5):1800-10. · 3.67 Impact Factor
Article: Engineering myocardial tissue.[Show abstract] [Hide abstract]
ABSTRACT: To create an artificial heart is one of the most ambitious dreams of the young field of tissue engineering, a dream that, when publicly announced in 1999 (LIFE initiative around M. Sefton), provoked as much compassion as scepticism in the scientific and lay press. Today, it is fair to state that the field is still far away from having built the "bioartificial heart." Nevertheless, substantial progress has been made over the past 10 years, and a realistic perspective exists to create 3-dimensional heart muscle equivalents that may not only serve as experimental models but could also be useful for cardiac regeneration.Circulation Research 01/2006; 97(12):1220-31. · 11.86 Impact Factor
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ABSTRACT: Cardiac tissue replacement therapy, although a promising novel approach for the potential treatment of heart failure, still suffers from insufficient contractile support to the failing myocardium. Here, we explore a strategy to improve contractile properties of engineered heart tissue (EHT) by S100A1 gene transfer. EHTs were generated from neonatal rat cardiomyocytes and transfected (MOI 10 PFU) with the S100A1 adenovirus (AdvS100A1, n = 25) while an adenovirus devoid of the S100A1 cDNA served as a control (AdvGFP, n = 30). Contractile properties of transfected EHTs were measured 7 days following gene transfer. Western blot analysis confirmed a 8.7 +/- 3.6-fold S100A1 protein overexpression in AdvS100A1-transfected EHTs (n = 4; P < 0.01) that increased maximal isometric force (mN; AdvGFP 0.175 +/- 0.03 vs. AdvS100A1 0.47 +/- 0.06; P < 0.05) at 0.4 mmol/L extracellular calcium concentration [Ca(2+)](e). In addition, S100A1 overexpression enhanced both maximal Ca(2+)-stimulated force generation (+81%; P < 0.05) and Ca(2+)-sensitivity of EHTs (EC50% [Ca(2+)](e) mM; AdvGFP 0.33 +/- 0.04 vs. AdvS100A1 0.21 +/- 0.0022; P < 0.05). The S100A1-mediated gain in basal graft contractility was preserved throughout a series of isoproterenol interventions (10(-9) to 10(-6) M). Physiological properties of EHTs resembling intact heart preparations were preserved. S100A1 gene transfer in EHT is feasible and augments contractile performance, while characteristic physiological features of EHT remain unchanged. Thus, specific genetic manipulation of tissue constructs prior to implantation should be part of an improved tissue replacement strategy in heart failure.The Journal of Gene Medicine 04/2004; 6(4):387-94. · 2.16 Impact Factor