Molecular and electrophysiological evaluation of human cardiomyocyte subtypes to facilitate generation of composite cardiac models.

Autor: Li J; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Wiesinger A; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Fokkert L; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Boukens BJ; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Verkerk AO; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.; Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Christoffels VM; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Boink GJJ; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.; Department of Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands., Devalla HD; Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of tissue engineering [J Tissue Eng] 2022 Oct 18; Vol. 13, pp. 20417314221127908. Date of Electronic Publication: 2022 Oct 18 (Print Publication: 2022).
DOI: 10.1177/20417314221127908
Abstrakt: Paucity of physiologically relevant cardiac models has limited the widespread application of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in drug development. Here, we performed comprehensive characterization of hiPSC-derived cardiomyocyte subtypes from 2D and 3D cultures and established a novel 3D model to study impulse initiation and propagation. Directed differentiation approaches were used to generate sinoatrial nodal (SANCM), atrial (ACM) and ventricular cardiomyocytes (VCM). Single cell RNA sequencing established that the protocols yield distinct cell populations in line with expected identities, which was also confirmed by electrophysiological characterization. In 3D EHT cultures of all subtypes, we observed prominent expression of stretch-responsive genes such as NPPA . Response to rate modulating drugs noradrenaline, carbachol and ivabradine were comparable in single cells and EHTs. Differences in the speed of impulse propagation between the subtypes were more pronounced in EHTs compared with 2D monolayers owing to a progressive increase in conduction velocities in atrial and ventricular cardiomyocytes, in line with a more mature phenotype. In a novel binary EHT model of pacemaker-atrial interface, the SANCM end of the tissue consistently paced the EHTs under baseline conditions, which was inhibited by ivabradine. Taken together, our data provide comprehensive insights into molecular and electrophysiological properties of hiPSC-derived cardiomyocyte subtypes, facilitating the creation of next generation composite cardiac models for drug discovery, disease modeling and cell-based regenerative therapies.
Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GJJB reports ownership interest in PacingCure B.V. The other authors report no conflict of interest.
(© The Author(s) 2022.)
Databáze: MEDLINE
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