Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation

Changsung Kim, Maryam Majdi, Peng Xia, Karen A. Wei, Maria Talantova, Sean Spiering, Brandon Nelson, Mark Mercola, Huei Sheng Vincent Chen

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Various types of cardiomyocytes undergo changes in automaticity and electrical properties during fetal heart development. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs), like fetal cardiomyocytes, are electrophysiologically immature and exhibit automaticity. We used hESC-CMs to investigate developmental changes in mechanisms of automaticity and to determine whether electrophysiological maturation is driven by an intrinsic developmental clock and/or is regulated by interactions with non-cardiomyocytes in embryoid bodies (EBs). We isolated pure populations of hESC-CMs from EBs by lentivirus-engineered Puromycin resistance at various stages of differentiation. Using pharmacological agents, calcium (Ca2+) imaging, and intracellular recording techniques, we found that intracellular Ca 2+-cycling mechanisms developed early and contributed to dominant automaticity throughout hESC-CM differentiation. Sarcolemmal ion channels evolved later upon further differentiation within EBs and played an increasing role in controlling automaticity and electrophysiological properties of hESC-CMs. In contrast to the development of intracellular Ca2+- handling proteins, ion channel development and electrophysiological maturation of hESC-CMs did not occur when hESC-CMs were isolated from EBs early and maintained in culture without further interaction with non-cardiomyocytes. Adding back non-cardiomyocytes to early-isolated hESC-CMs rescued the arrest of electrophysiological maturation, indicating that non-cardiomyocytes in EBs drive electrophysiological maturation of early hESC-CMs. Non-cardiomyocytes in EBs contain most cell types present in the embryonic heart that are known to influence early cardiac development. Our study is the first to demonstrate that non-cardiomyocytes influence electrophysiological maturation of early hESC-CMs in cultures. Defining the nature of these extrinsic signals will aid in the directed maturation of immature hESC-CMs to mitigate arrhythmogenic risks of cell-based therapies.

Original languageEnglish (US)
Pages (from-to)783-795
Number of pages13
JournalStem Cells and Development
Volume19
Issue number6
DOIs
StatePublished - Jun 1 2010

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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    Kim, C., Majdi, M., Xia, P., Wei, K. A., Talantova, M., Spiering, S., Nelson, B., Mercola, M., & Chen, H. S. V. (2010). Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cells and Development, 19(6), 783-795. https://doi.org/10.1089/scd.2009.0349