title: Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients.
abstract: OBJECTIVE
  Myocardial cell replacement therapies are hampered by a paucity of sources for human cardiomyocytes and by the expected immune rejection of allogeneic cell grafts. The ability to derive patient-specific human-induced pluripotent stem cells (hiPSCs) may provide a solution to these challenges. We aimed to derive hiPSCs from heart failure (HF) patients, to induce their cardiomyocyte differentiation, to characterize the generated hiPSC-derived cardiomyocytes (hiPSC-CMs), and to evaluate their ability to integrate with pre-existing cardiac tissue.
  
  
  RESULTS
  Dermal fibroblasts from two HF patients were reprogrammed by retroviral delivery of Oct4, Sox2, and Klf4 or by using an excisable polycistronic lentiviral vector. The resulting HF-hiPSCs displayed adequate reprogramming properties and could be induced to differentiate into cardiomyocytes with the same efficiency as control hiPSCs (derived from human foreskin fibroblasts). Gene expression and immunostaining studies confirmed the cardiomyocyte phenotype of the differentiating HF-hiPSC-CMs. Multi-electrode array recordings revealed the development of a functional cardiac syncytium and adequate chronotropic responses to adrenergic and cholinergic stimulation. Next, functional integration and synchronized electrical activities were demonstrated between hiPSC-CMs and neonatal rat cardiomyocytes in co-culture studies. Finally, in vivo transplantation studies in the rat heart revealed the ability of the HF-hiPSC-CMs to engraft, survive, and structurally integrate with host cardiomyocytes.
  
  
  CONCLUSIONS
  Human-induced pluripotent stem cells can be established from patients with advanced heart failure and coaxed to differentiate into cardiomyocytes, which can integrate with host cardiac tissue. This novel source for patient-specific heart cells may bring a unique value to the emerging field of cardiac regenerative medicine.
authors.affiliation: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Zwi-Dantsis
authors.forename: Irit
authors.initials: I
authors.lastname: Huber
authors.forename: Manhal
authors.initials: M
authors.lastname: Habib
authors.forename: Aaron
authors.initials: A
authors.lastname: Winterstern
authors.forename: Amira
authors.initials: A
authors.lastname: Gepstein
authors.forename: Gil
authors.initials: G
authors.lastname: Arbel
authors.forename: Lior
authors.initials: L
authors.lastname: Gepstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D065150:Cellular Reprogramming / Q000187:drug effects; D005260:Female; D005822:Genetic Vectors; D006333:Heart Failure / Q000473:pathology* / Q000628:therapy; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D059785:Karyotype; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology*; D050814:Octamer Transcription Factor-3 / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055748:SOXB1 Transcription Factors / Q000494:pharmacology; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors