Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy

Ruilian Ma, Jialiang Liang, Wei Huang, Linlin Guo, Wenfeng Cai, Lei Wang, Christian Paul, Huang Tian Yang, Ha Won Kim, Yigang Wang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aims: Electrical stimulation (EleS) can promote cardiac differentiation, but the underlying mechanism is not well known. This study investigated the effect of EleS on cardiomyocyte (CM) differentiation of human induced pluripotent stem cells (hiPSCs) and evaluated the therapeutic effects for the treatment of myocardial infarction (MI). Results: Cardiac differentiation of hiPSCs was induced with EleS after embryoid body formation. Spontaneously beating hiPSCs were observed as early at 2 days when treated with EleS compared with control treatment. The cardiac differentiation efficiency of hiPSCs was significantly enhanced by EleS. In addition, the functional maturation of hiPSC-CMs under EleS was confirmed by calcium indicators, intracellular Ca 2+ levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca 2+ /PKC/ERK pathways, as revealed by RNA sequencing, quantitative polymerase chain reaction, and Western blotting. After transplantation in immunodeficient MI mice, EleS-preconditioned hiPSC-derived cells significantly improved cardiac function and attenuated expansion of infarct size. The preconditioned hiPSC-derived CMs were functionally integrated with the host heart. Innovation: We show EleS as an efficacious time-saving approach for CM generation. The global RNA profiling shows that EleS can accelerate cardiac differentiation of hiPSCs through activation of multiple pathways. The cardiac-mimetic electrical signals will provide a novel approach to generate functional CMs and facilitate cardiac tissue engineering for successful heart regeneration. Conclusion: EleS can enhance efficiency of cardiac differentiation in hiPSCs and promote CM maturation. The EleS-preconditioned CMs emerge as a promising approach for clinical application in MI treatment. Antioxid. Redox Signal. 28, 371-384.

Original languageEnglish (US)
Pages (from-to)371-384
Number of pages14
JournalAntioxidants and Redox Signaling
Volume28
Issue number5
DOIs
StatePublished - Feb 10 2018

Fingerprint

Induced Pluripotent Stem Cells
Stem cells
Electric Stimulation
Myocardial Infarction
Therapeutics
Cardiac Myocytes
Chemical activation
RNA
Polymerase chain reaction
Tissue engineering
Embryoid Bodies
RNA Sequence Analysis
Genes
Innovation
MAP Kinase Signaling System
Calcium
Therapeutic Uses
Tissue Engineering
Oxidation-Reduction
Regeneration

Keywords

  • calcium pathways
  • cardiomyocytes
  • cellular differentiation
  • electric stimulation
  • induced pluripotent stem cells
  • myocardial infarction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy. / Ma, Ruilian; Liang, Jialiang; Huang, Wei; Guo, Linlin; Cai, Wenfeng; Wang, Lei; Paul, Christian; Yang, Huang Tian; Kim, Ha Won; Wang, Yigang.

In: Antioxidants and Redox Signaling, Vol. 28, No. 5, 10.02.2018, p. 371-384.

Research output: Contribution to journalArticle

Ma, Ruilian ; Liang, Jialiang ; Huang, Wei ; Guo, Linlin ; Cai, Wenfeng ; Wang, Lei ; Paul, Christian ; Yang, Huang Tian ; Kim, Ha Won ; Wang, Yigang. / Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy. In: Antioxidants and Redox Signaling. 2018 ; Vol. 28, No. 5. pp. 371-384.
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AU - Cai, Wenfeng

AU - Wang, Lei

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AU - Yang, Huang Tian

AU - Kim, Ha Won

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AB - Aims: Electrical stimulation (EleS) can promote cardiac differentiation, but the underlying mechanism is not well known. This study investigated the effect of EleS on cardiomyocyte (CM) differentiation of human induced pluripotent stem cells (hiPSCs) and evaluated the therapeutic effects for the treatment of myocardial infarction (MI). Results: Cardiac differentiation of hiPSCs was induced with EleS after embryoid body formation. Spontaneously beating hiPSCs were observed as early at 2 days when treated with EleS compared with control treatment. The cardiac differentiation efficiency of hiPSCs was significantly enhanced by EleS. In addition, the functional maturation of hiPSC-CMs under EleS was confirmed by calcium indicators, intracellular Ca 2+ levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca 2+ /PKC/ERK pathways, as revealed by RNA sequencing, quantitative polymerase chain reaction, and Western blotting. After transplantation in immunodeficient MI mice, EleS-preconditioned hiPSC-derived cells significantly improved cardiac function and attenuated expansion of infarct size. The preconditioned hiPSC-derived CMs were functionally integrated with the host heart. Innovation: We show EleS as an efficacious time-saving approach for CM generation. The global RNA profiling shows that EleS can accelerate cardiac differentiation of hiPSCs through activation of multiple pathways. The cardiac-mimetic electrical signals will provide a novel approach to generate functional CMs and facilitate cardiac tissue engineering for successful heart regeneration. Conclusion: EleS can enhance efficiency of cardiac differentiation in hiPSCs and promote CM maturation. The EleS-preconditioned CMs emerge as a promising approach for clinical application in MI treatment. Antioxid. Redox Signal. 28, 371-384.

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