Extracellular macrostructure anisotropy improves cardiac tissue-like construct function and phenotypic cellular maturation.

Regenerative cardiac tissue is a promising field of study with translational potential as a therapeutic option for myocardial repair after injury, however, poor electrical and contractile function has limited translational utility. Emerging research suggests scaffolds that recapitulate the structure of the native myocardium improve physiological function. Engineered cardiac constructs with anisotropic extracellular architecture demonstrate improved tissue contractility, signaling synchronicity, and cellular organization when compared to constructs with reduced architectural order. The complexity of scaffold fabrication, however, limits isolated variation of individual structural and mechanical characteristics. Thus, the isolated impact of scaffold macroarchitecture on tissue function is poorly understood. Here, we produce isotropic and aligned collagen scaffolds seeded with embryonic stem cell derived cardiomyocytes (hESC-CM) while conserving all confounding physio-mechanical features to independently assess the effects of macroarchitecture on tissue function. We quantified spatiotemporal tissue function through calcium signaling and contractile strain. We further examined intercellular organization and intracellular development. Aligned tissue constructs facilitated improved signaling synchronicity and directional contractility as well as dictated uniform cellular alignment. Cells on aligned constructs also displayed phenotypic and genetic markers of increased maturity. Our results isolate the influence of scaffold macrostructure on tissue function and inform the design of optimized cardiac tissue for regenerative and model medical systems.

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Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sanjay Sinha reports financial support was provided by British Heart Foundation Oxbridge Centre for Regenerative Medicine. Sanjay Sinha reports financial support was provided by British Heart Foundation Senior Fellowship. Sanjay Sinha reports financial support was provided by British Heart Foundation Centre for Cardiovascular Research Excellence. Maria Colzani reports financial support was provided by British Heart Foundation Oxbridge Centre for Regenerative Medicine. Maria Colzani reports financial support was provided by British Heart Foundation. Jamie A. Cyr reports financial support was provided by the Gates Cambridge Fellowship. Ruth E. Cameron reports financial support was provided by the Engineering and Physical Sciences Research Council Established Career Fellowship. Serena M. Best reports financial support was provided by the Engineering and Physical Sciences Research Council Established Career Fellowship. Vera Graup reports financial support was provided by the British Heart Foundation Cambridge Centre of Excellence. Sanjay Sinha reports financial support was provided by the Wellcome Trust Medical Research Council Cambridge Stem Cell Institute.