Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype

Cardiac cell lines and primary cells are widely used in cardiovascular research. Despite increasing number of publications using these models, comparative characterization of these cell lines has not been performed, therefore, their limitations are undetermined. We aimed to compare cardiac cell line...

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Published in:Journal of molecular and cellular cardiology 2022-04, Vol.165, p.19-30
Main Authors: Onódi, Zsófia, Visnovitz, Tamás, Kiss, Bernadett, Hambalkó, Szabolcs, Koncz, Anna, Ágg, Bence, Váradi, Barnabás, Tóth, Viktória É., Nagy, Regina N., Gergely, Tamás G., Gergő, Dorottya, Makkos, András, Pelyhe, Csilla, Varga, Nóra, Reé, Dóra, Apáti, Ágota, Leszek, Przemyslaw, Kovács, Tamás, Nagy, Nándor, Ferdinandy, Péter, Buzás, Edit I., Görbe, Anikó, Giricz, Zoltán, Varga, Zoltán V.
Format: Article
Language:English
Subjects:
AC16
Cardiomyocyte
H9C2
HL-1
Primary cell culture
Stem cell
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Summary:Cardiac cell lines and primary cells are widely used in cardiovascular research. Despite increasing number of publications using these models, comparative characterization of these cell lines has not been performed, therefore, their limitations are undetermined. We aimed to compare cardiac cell lines to primary cardiomyocytes and to mature cardiac tissues in a systematic manner. Cardiac cell lines (H9C2, AC16, HL-1) were differentiated with widely used protocols. Left ventricular tissue, neonatal primary cardiomyocytes, and human induced pluripotent stem cell-derived cardiomyocytes served as reference tissue or cells. RNA expression of cardiac markers (e.g. Tnnt2, Ryr2) was markedly lower in cell lines compared to references. Differentiation induced increase in cardiac- and decrease in embryonic markers however, the overall transcriptomic profile and annotation to relevant biological processes showed consistently less pronounced cardiac phenotype in all cell lines in comparison to the corresponding references. Immunocytochemistry confirmed low expressions of structural protein sarcomeric alpha-actinin, troponin I and caveolin-3 in cell lines. Susceptibility of cell lines to sI/R injury in terms of viability as well as mitochondrial polarization differed from the primary cells irrespective of their degree of differentiation. Expression patterns of cardiomyocyte markers and whole transcriptomic profile, as well as response to sI/R, and to hypertrophic stimuli indicate low-to-moderate similarity of cell lines to primary cells/cardiac tissues regardless their differentiation. Low resemblance of cell lines to mature adult cardiac tissue limits their potential use. Low translational value should be taken into account while choosing a particular cell line to model cardiomyocytes. [Display omitted] •Immortalized cardiac cell lines show low resemblance to mature cardiac cells.•Organized sarcomeric structure is detectable in HL-1 cells but not in H9C2 or AC16.•Differentiation of AC16 or H9C2 induces minor changes towards cardiac phenotype.•Functional tests reveal the restricted responsiveness of all the cardiac cell lines.•This is the first systematic study showing major limitations of cardiac cell lines.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2021.12.007