title: Design and formulation of functional pluripotent stem cell-derived cardiac microtissues.
abstract: Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function.
authors.affiliation: Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada M5S 3G9.
authors.forename: Nimalan
authors.initials: N
authors.lastname: Thavandiran
authors.forename: Nicole
authors.initials: N
authors.lastname: Dubois
authors.forename: Alexander
authors.initials: A
authors.lastname: Mikryukov
authors.forename: Stéphane
authors.initials: S
authors.lastname: Massé
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beca
authors.forename: Craig A
authors.initials: CA
authors.lastname: Simmons
authors.forename: Vikram S
authors.initials: VS
authors.lastname: Deshpande
authors.forename: J Patrick
authors.initials: JP
authors.lastname: McGarry
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.forename: Kumaraswamy
authors.initials: K
authors.lastname: Nanthakumar
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Keller
authors.forename: Milica
authors.initials: M
authors.lastname: Radisic
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
mesh_terms: D001696:Biomechanical Phenomena; D060833:Cellular Microenvironment / Q000502:physiology*; D004558:Electric Stimulation; D020342:Finite Element Analysis; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D018800:Thy-1 Antigens / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D018800:Thy-1 Antigens; D014157:Transcription Factors
keywords: arrhythmia disease model; cardiac toxicity; heart regeneration; microfabrication; tissue engineering