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

105 Citations (Scopus)

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
Externally publishedYes

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Cardiac Myocytes
Embryoid Bodies
Ion Channels
Human Embryonic Stem Cells
Fetal Heart
Puromycin
Lentivirus
Cell- and Tissue-Based Therapy
Fetal Development
Pharmacology
Calcium

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. / Kim, Changsung; Majdi, Maryam; Xia, Peng; Wei, Karen A.; Talantova, Maria; Spiering, Sean; Nelson, Brandon; Mercola, Mark; Chen, Huei Sheng Vincent.

In: Stem Cells and Development, Vol. 19, No. 6, 01.06.2010, p. 783-795.

Research output: Contribution to journalArticle

Kim, C, Majdi, M, Xia, P, Wei, KA, Talantova, M, Spiering, S, Nelson, B, Mercola, M & Chen, HSV 2010, 'Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation', Stem Cells and Development, vol. 19, no. 6, pp. 783-795. https://doi.org/10.1089/scd.2009.0349
Kim, Changsung ; Majdi, Maryam ; Xia, Peng ; Wei, Karen A. ; Talantova, Maria ; Spiering, Sean ; Nelson, Brandon ; Mercola, Mark ; Chen, Huei Sheng Vincent. / Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. In: Stem Cells and Development. 2010 ; Vol. 19, No. 6. pp. 783-795.
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AU - Spiering, Sean

AU - Nelson, Brandon

AU - Mercola, Mark

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