Conditional immortalization of human atrial myocytes for the generation of in vitro models of atrial fibrillation

Niels Harlaar, Sven O. Dekker, Juan Zhang, Rebecca R. Snabel, Marieke W. Veldkamp, Arie O. Verkerk, Carla Cofino Fabres, Verena Schwach, Lente J. S. Lerink, Mathilde R. Rivaud, Aat A. Mulder, Willem E. Corver, Marie Jose T. H. Goumans, Dobromir Dobrev, Robert J. M. Klautz, Martin J. Schalij, Gert Jan C. Veenstra, Robert Passier, Thomas J. van Brakel, Daniel A. PijnappelsAntoine A. F. de Vries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The lack of a scalable and robust source of well-differentiated human atrial myocytes constrains the development of in vitro models of atrial fibrillation (AF). Here we show that fully functional atrial myocytes can be generated and expanded one-quadrillion-fold via a conditional cell-immortalization method relying on lentiviral vectors and the doxycycline-controlled expression of a recombinant viral oncogene in human foetal atrial myocytes, and that the immortalized cells can be used to generate in vitro models of AF. The method generated 15 monoclonal cell lines with molecular, cellular and electrophysiological properties resembling those of primary atrial myocytes. Multicellular in vitro models of AF generated using the immortalized atrial myocytes displayed fibrillatory activity (with activation frequencies of 6–8 Hz, consistent with the clinical manifestation of AF), which could be terminated by the administration of clinically approved antiarrhythmic drugs. The conditional cell-immortalization method could be used to generate functional cell lines from other human parenchymal cells, for the development of in vitro models of human disease.
Original languageEnglish
Pages (from-to)389-402
Number of pages14
JournalNature Biomedical Engineering
Volume6
Early online date6 Jan 2022
DOIs
Publication statusPublished - Apr 2022

Keywords

  • 22/2 OA procedure

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