Modeling long QT syndrome type 2 on-a-chip via indepth assessment of isogenic gene-edited 3D cardiac tissues
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University of Arizona, College of MedicineIssue Date
2022-12-16
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Veldhuizen, J., Mann, H. F., Karamanova, N., Van Horn, W. D., Migrino, R. Q., Brafman, D., & Nikkhah, M. (2022). Modeling long QT syndrome type 2 on-a-chip via indepth assessment of isogenic gene-edited 3D cardiac tissues. Science Advances, 8(50).Journal
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© 2022. The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Long QT syndrome (LQTS) is a cardiovascular disease characterized by QT interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in KCNH2, the gene that encodes for hERG (Kv11.1), which lead to onset of LQTS type 2 (LQTS2). In this work, we developed a LQTS2-diseased tissue-on-a-chip model, using 3D coculture of isogenic stem cell-derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily, we created a hiPSC line with R531W mutation in KCNH2 using CRISPR-Cas9 gene-editing technique and characterized the resultant differentiated CMs and CFs. A deficiency in hERG trafficking was identified in KCNH2-edited hiPSC-CMs, revealing a possible mechanism of R531W mutation in LQTS2 pathophysiology. Following creation of a 3D LQTS2 tissue-on-a-chip, the tissues were extensively characterized, through analysis of calcium handling and response to β-agonist. Furthermore, attempted phenotypic rescue via pharmacological intervention of LQTS2 on a chip was investigated. © 2022 The Authors.Note
Open access journalISSN
2375-2548PubMed ID
36525500Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1126/sciadv.abq6720
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Except where otherwise noted, this item's license is described as © 2022. The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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