Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes

Deborah Lieu, Ji Dong Fu, Nipavan Chiamvimonvat, Kelvin Chan Tung, Gregory P. McNerney, Thomas R Huser, Gordon Keller, Chi Wing Kong, Ronald A. Li

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Background - Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. Methods and Results - Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4-depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated (INa +/ICaL +/IKr +/I NCX +/If +/Ito +/IK1 -/IKs -), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K+ current (I K1) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba2+-sensitive IK1 and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation. Conclusions - By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.

Original languageEnglish (US)
Pages (from-to)191-201
Number of pages11
JournalCirculation: Arrhythmia and Electrophysiology
Volume6
Issue number1
DOIs
StatePublished - Feb 2013

Fingerprint

Pluripotent Stem Cells
Cardiac Myocytes
Action Potentials
Embryoid Bodies
Phenotype
Induced Pluripotent Stem Cells
Drug Discovery
Membrane Potentials
Cues
Pharmacology
Safety
Cell Line
Human Embryonic Stem Cells
Genes

Keywords

  • Cardiac
  • Electrophysiology
  • Human
  • Myocytes
  • Pluripotent stem cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Medicine(all)

Cite this

Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. / Lieu, Deborah; Fu, Ji Dong; Chiamvimonvat, Nipavan; Tung, Kelvin Chan; McNerney, Gregory P.; Huser, Thomas R; Keller, Gordon; Kong, Chi Wing; Li, Ronald A.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 6, No. 1, 02.2013, p. 191-201.

Research output: Contribution to journalArticle

Lieu, Deborah ; Fu, Ji Dong ; Chiamvimonvat, Nipavan ; Tung, Kelvin Chan ; McNerney, Gregory P. ; Huser, Thomas R ; Keller, Gordon ; Kong, Chi Wing ; Li, Ronald A. / Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. In: Circulation: Arrhythmia and Electrophysiology. 2013 ; Vol. 6, No. 1. pp. 191-201.
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