title: Integrated platform for functional monitoring of biomimetic heart sheets derived from human pluripotent stem cells.
abstract: We present an integrated platform comprised of a biomimetic substrate and physiologically aligned human pluripotent stem cell-derived cardiomyocytes (CMs) with optical detection and algorithms to monitor subtle changes in cardiac properties under various conditions. In the native heart, anisotropic tissue structures facilitate important concerted mechanical contraction and electrical propagation. To recapitulate the architecture necessary for a physiologically accurate heart response, we have developed a simple way to create large areas of aligned CMs with improved functional properties using shrink-wrap film. Combined with simple bright field imaging, obviating the need for fluorescent labels or beads, we quantify and analyze key cardiac contractile parameters. To evaluate the performance capabilities of this platform, the effects of two drugs, E-4031 and isoprenaline, were examined. Cardiac cells supplemented with E-4031 exhibited an increase in contractile duration exclusively due to prolonged relaxation peak. Notably, cells aligned on the biomimetic platform responded detectably down to a dosage of 3 nM E-4031, which is lower than the IC50 in the hERG channel assay. Cells supplemented with isoprenaline exhibited increased contractile frequency and acceleration. Interestingly, cells grown on the biomimetic substrate were more responsive to isoprenaline than those grown on the two control surfaces, suggesting topography may help induce more mature ion channel development. This simple and low-cost platform could thus be a powerful tool for longitudinal assays as well as an effective tool for drug screening and basic cardiac research.
authors.affiliation: Department of Chemical Engineering and Materials Science, University of California, Irvine, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chen
authors.forename: Eugene
authors.initials: E
authors.lastname: Lee
authors.forename: Roger
authors.initials: R
authors.lastname: Tu
authors.forename: Kevin
authors.initials: K
authors.lastname: Santiago
authors.forename: Anna
authors.initials: A
authors.lastname: Grosberg
authors.forename: Charless
authors.initials: C
authors.lastname: Fowlkes
authors.forename: Michelle
authors.initials: M
authors.lastname: Khine
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D032701:Biomimetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D020128:Inhibitory Concentration 50; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D007545:Isoproterenol
keywords: Cardiomyocytes; Contractile properties; Drug screening; Human pluripotent stem cells