title: Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy.
abstract: 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).
  
  
  
  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 Ca2+levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca2+/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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Ruilian
authors.initials: R
authors.lastname: Ma
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Liang
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Linlin
authors.initials: L
authors.lastname: Guo
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Christian
authors.initials: C
authors.lastname: Paul
authors.affiliation: 2 Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM) , Shanghai, China .
authors.forename: Huang-Tian
authors.initials: HT
authors.lastname: Yang
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000528:radiation effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006321:Heart / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000528:radiation effects / Q000637:transplantation*; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000528:radiation effects / Q000637:transplantation*; D012038:Regeneration / Q000528:radiation effects; D023822:Tissue Engineering
keywords: calcium pathways; cardiomyocytes; cellular differentiation; electric stimulation; induced pluripotent stem cells; myocardial infarction