Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue. Issue 20 (15th November 2016)

• Record Type: Journal Article
• Authors: Ruan, Jia-Ling; Tulloch, Nathaniel L.; Razumova, Maria V.; Saiget, Mark; Muskheli, Veronica; Pabon, Lil; Reinecke, Hans; Regnier, Michael; Murry, Charles E.
• Is Part Of: Circulation. Volume 134:Issue 20(2016)
• Publication Date: 2016-11-15
• Subjects: cardiomyocyte hypertrophy -- electrical stimulation -- human myocardium -- stem cell -- stress -- tissue engineering; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.114.014998
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Background: Tissue engineering enables the generation of functional human cardiac tissue with cells derived in vitro in combination with biocompatible materials. Human-induced pluripotent stem cell-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 electric pacing on the maturation of human-induced pluripotent stem cell-derived cardiac tissues. Methods: Cardiomyocytes derived from human-induced pluripotent stem cells were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electric 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/mm 2 vs 0.055±0.009 mN/mm 2 for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 (Sarco/Endoplasmic Reticulum Calcium ATPase 2) expression, which correlated with a less negative force-frequency relationship. When electric pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm 2 ), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 (Ryanodine Receptor 2) and SERCA2 further increased by combined static stress and electric stimulation. Conclusions: These studies demonstrate that electric pacing and mechanical stimulation promote maturation of the structural, mechanical, and force generation properties of human-induced pluripotent stem cell-derived cardiac tissues. Abstract : Supplemental Digital Content is available in the text.