Functional maturation of human pluripotent stem cell derived cardiomyocytes invitro - Correlation between contraction force andelectrophysiology

Marcelo C. Ribeiro, Leon G. Tertoolen, Juan A. Guadix, Milena Bellin, Georgios Kosmidis, Cristina D'Aniello, Jantine Monshouwer-Kloots, Marie Jose Goumans, Yu li Wang, Adam W. Feinberg, Christine L. Mummery, Robert Passier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

121 Citations (Scopus)
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Abstract

Cardiomyocytes from human pluripotent stem cells (hPSC-CM) have many potential applications in disease modelling and drug target discovery but their phenotypic similarity to early fetal stages of cardiac development limits their applicability. In this study we compared contraction stresses of hPSC-CM to 2nd trimester human fetal derived cardiomyocytes (hFetal-CM) by imaging displacement of fluorescent beads by single contracting hPSC-CM, aligned by microcontact-printing on polyacrylamide gels. hPSC-CM showed distinctly lower contraction stress than cardiomyocytes isolated from hFetal-CM. To improve maturation of hPSC-CM invitro we made use of commercial media optimized for cardiomyocyte maturation, which promoted significantly higher contraction stress in hPSC-compared with hFetal-CM. Accordingly, other features of cardiomyocyte maturation were observed, most strikingly increased upstroke velocities and action potential amplitudes, lower resting membrane potentials, improved sarcomeric organization and alterations in cardiac-specific gene expression. Performing contraction force and electrophysiology measurements on individual cardiomyocytes revealed strong correlations between an increase in contraction force and a rise of the upstroke velocity and action potential amplitude and with a decrease in the resting membrane potential. We showed that under standard differentiation conditions hPSC-CM display lower contractile force than primary hFetal-CM and identified conditions under which a commercially available culture medium could induce molecular, morphological and functional maturation of hPSC-CM invitro. These results are an important contribution for full implementation of hPSC-CM in cardiac disease modelling and drug discovery.

Original languageEnglish
Pages (from-to)138-150
Number of pages13
JournalBiomaterials
Volume51
DOIs
Publication statusPublished - 1 Jan 2015
Externally publishedYes

Keywords

  • Cardiomyocyte contraction force
  • Cardiomyocyte maturation
  • Human fetal cardiomyocytes
  • Human pluripotent stem cells

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