Trends in cardiovascular engineering: organizing the human heart

Abstract

The regulation of heart growth through the interaction of cell types, matrix molecules, and mechanical cues is poorly understood, yet is necessary for the heart to reach its proper size and function. Using mechanical load and vascular cell co-culture in combination with a tissue engineering approach, we have recently been able to generate organized human myocardium in vitro and to modulate cardiomyocyte alignment, proliferation, and hypertrophy within the engineered tissue construct; further, we measured contractile function and the force-length dependence of the engineered tissue as a whole. The goal of these studies has been to characterize in vitro models of human cardiac development and to work towards human therapeutics using organized, vascularized, contractile human cardiac tissue. This review will touch on the current state of knowledge in this field, give an overview of the results of our own recent findings, and present areas of active investigation and new directions for future research.

Figure 1. Bioengineered cardiovascular progenitor tissue constructs mature into cardiovascular tissue

A, Undifferentiated human iPS cells of the IMR90 line were differentiated into cardiomyocytes using activin A and BMP4 and stained for the sarcomeric protein alpha-actinin (green) and the cardiomyocyte transcription factor Nkx2.5 (red). B, hiPSC-derived cardiac tissue graft and human fetal cardiac tissue, both stained for alpha-actinin. C, Engrafted cardiovascular tissue construct with human endothelium (CD31, green) perfused with host red blood cells (Ter119, red). D, Contractility of human cardiac tissue construct generated with cardiomyocytes, endothelial cells, and stromal cells is increased with stepwise increases in preparation length. E, Passive force (baseline) recorded 15 seconds after each acute stretch increased with increasing length. F, Active force twitch height increased with increasing length, similar to Starling curves generated from native myocardium (R² = 0.99 for initial 20% length increase).