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Circulation. 2016 Nov 15;134(20):1557-1567. Epub 2016 Oct 13.

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

Author information

1
From Department of Bioengineering (J.-L.R, M.V.R., M.R., C.E.M.), Program in Molecular and Cellular Biology (N.L.T.), Department of Pathology (N.L.T., M.R., V.M., L.P., H.R., C.E.M.), and Department of Medicine/Cardiology (C.E.M.), Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle.
2
From Department of Bioengineering (J.-L.R, M.V.R., M.R., C.E.M.), Program in Molecular and Cellular Biology (N.L.T.), Department of Pathology (N.L.T., M.R., V.M., L.P., H.R., C.E.M.), and Department of Medicine/Cardiology (C.E.M.), Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle. murry@uw.edu mregnier@uw.edu.

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/mm2 vs 0.055±0.009 mN/mm2 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/mm2), 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.

KEYWORDS:

cardiomyocyte hypertrophy; electrical stimulation; human myocardium; stem cell; stress; tissue engineering

PMID:
27737958
PMCID:
PMC5123912
DOI:
10.1161/CIRCULATIONAHA.114.014998
[Indexed for MEDLINE]
Free PMC Article

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