Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts

Abstract

The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

Endothelial cells guided by immobilized gradients of vascular endothelial growth factor on porous collagen scaffolds

“…The constructs appeared to delay the ventricular thinning and led to a reduced increase in the diastolic volume and pressure compared to the sham groups [25]. The constructs were about ~ 400 µm thick and showed vessel formation by the donor cells that supported the construct beyond the 100 µm mark of diffusion limit [26].…”

Tissue Contraction Force Microscopy for Optimization of Engineered Cardiac Tissue

“…This has been shown to improve ECT twitch force production. 26 ECTs formed as hiPSC-CMcontaining fibrin gels were able to displace the microspherecontaining PDMS, which allowed for indirect quantification of the twitch force. While not reported, contraction and relaxation rates can be directly quantified and compared.…”

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

“…Furthermore, these EHTs can be stacked together in various geometries to increase graft size and then stitch the graft to an infarcted heart. Epicardial mapping has shown that paced EHTs propagate electrical signals to the surrounding myocardium, and that these grafts do not lead to arrhythmia [74]. Moreover, echocardiograph and MRI indicated reduced left ventricular dilation and end diastolic volume.…”

“…1c, d), and then use it to surgically repair the diseased myocardium. Several laboratories are successfully moving toward this goal [48,66,[73][74][75][76]. For example, engineered heart tissue grafts (EHTs) have been developed by seeding neonatal cardiomyocytes in circular molds with collagen and Matrigel, and then culturing the formed rings in a mechanical stretch device [73].…”

“…Recent modifications to EHT generation, using a mixed cell population with fibroblasts, smooth muscle cells, and endothelial cells, have resulted in superior contractile performance over cardiomyocyte samples alone [66]. Moreover, the creation of EHT from ESC and successful engraftment of these ESC-EHT into the working myocardium has also been reported [74].…”