Dataset Information

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling.

ABSTRACT: Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6456036 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling.

Zhao Yimu Y Rafatian Naimeh N Feric Nicole T NT Cox Brian J BJ Aschar-Sobbi Roozbeh R Wang Erika Yan EY Aggarwal Praful P Zhang Boyang B Conant Genevieve G Ronaldson-Bouchard Kacey K Pahnke Aric A Protze Stephanie S Lee Jee Hoon JH Davenport Huyer Locke L Jekic Danica D Wickeler Anastasia A Naguib Hani E HE Keller Gordon M GM Vunjak-Novakovic Gordana G Broeckel Ulrich U Backx Peter H PH Radisic Milica M

Cell 20190124 4

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca<sup>2 ...[more]

PMID: 30686581

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Project description:IntroductionAlthough atrial fibrillation is the most prevalent disorder of electrical conduction, the mechanisms behind atrial arrhythmias remain elusive. To address this challenge, we developed a robust in vitro model of 3D atrial microtissue from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and evaluated chamber-specific chemical responses experimentally and computationally.MethodsWe differentiated atrial and ventricular cardiomyocytes (aCMs/vCMs) from GCaMP6f-expressing hiPSCs and assessed spontaneous AP activity using fluorescence imaging. Self-assembling 3D microtissues were formed with lactate purified CMs and 5% human cardiac fibroblasts and electrically stimulated for one week before high resolution action potential (AP) optical mapping. AP responses to the atrial-specific potassium repolarizing current I Kur-blocker 4-Aminopyridine (4-AP) and funny current I f-blocker Ivabradine were characterized within their therapeutic window. Finally, we expanded upon a published hiPSC-CM computational model by incorporating the atrial-specific I Kur current, modifying ion channel conductances to match the AP waveforms of our microtissues, and employing the updated model to reinforce our experimental findings.ResultsHigh purity CMs (> 75% cTnT+) demonstrated subtype specification by MLC2v expression. Spontaneous beating rates significantly decreased following 3D microtissue formation, with atrial microtissues characterized by their faster spontaneous beating rate, slower AP rise time, and shorter AP duration (APD) compared to ventricular microtissues. We measured atrial-specific responses, including dose-dependent APD prolongation with 4-AP treatment and dose-dependent reduction in spontaneous activity post-Ivabradine treatment.ConclusionThe presented in vitro platform for screening atrial-specific responses is both robust and sensitive, with high throughput, enabling studies focused at elucidating the mechanisms underlying atrial arrhythmias.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-021-00703-x.

Dataset Information

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling.

Publications

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling.

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