Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue

Abstract

Background Tissue engineering enables the generation of functional human cardiac tissue using cells derived in vitro in combination with biocompatible materials. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications. Here we sought to study the effect of mechanical conditioning and electrical pacing on the maturation of hiPSC-derived cardiac tissues. Methods Cardiomyocytes derived from hiPSCs were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electrical pacing conditions. Results The engineered human myocardium exhibits Frank-Starling-type force-length relationships. After 2 weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility (0.63±0.10 mN/mm2 vs 0.055±0.009 mN/mm2 for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 expression, which correlated with a less negative force-frequency relationship. When electrical pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm2), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 and SERCA2 further increased by combined static stress and electrical stimulation. Conclusions These studies demonstrate that electrical pacing and mechanical stimulation promote maturation of the structural, mechanical and force generation properties of hiPSC-derived cardiac tissues.

Myocardial Tissue Engineering With Cells Derived From Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold

“…Tissue engineers are beginning to improve the effectiveness of MTE engineering for regenerative myocardial therapies 1–3 by developing techniques that can enhance the engraftment, improve the MTE maturation 4, 5 and long-term functional benefits. 6, 7 These efforts may be aided by incorporating some of the more complex features of the myocardial extracellular matrix (ECM) into the tissue’s design.…”

Rapid Electrical Stimulation Increased Cardiac Apoptosis Through Disturbance of Calcium Homeostasis and Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Previously, it was suggested that electrical stimulation promotes cardiac differentiation and maturation of hiPSC-derived cardiomyocytes [40][41][42]. Ruan et al [41] reported that electrical stimulation promotes force maturation of induced pluripotent stem cell-derived cardiac tissue; however, the cardiomyocytes used in this study were only 2 or 3 weeks old.…”

“…Ruan et al [41] reported that electrical stimulation promotes force maturation of induced pluripotent stem cell-derived cardiac tissue; however, the cardiomyocytes used in this study were only 2 or 3 weeks old. Damián Hernández et al [42] reported that electrical stimulation promoted cardiac differentiation; however, the parameters of electrical stimulation were set at 1 Hz and for a very short period of approximately 15 min.…”

One Stride Forward

“…Multiple components of excitation-contraction coupling must be integrated for this phenomenon, including an increased calcium influx via the L-type calcium channel, increased levels of sarcoendoplasmic reticulum calcium ATPase (SERCA), increased PLB, and potentially, reduced Na/Ca exchange. While our group had recently matured engineered human heart muscle to the point where the FFR went from negative to flat 11 , to our knowledge, this is the first demonstration of a positive FFR in engineered human myocardium.…”