title: Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model.
abstract: BACKGROUND
  Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are a promising source of cells for regenerating myocardium. However, several issues, especially the large-scale preparation of hiPS-CMs and elimination of undifferentiated iPS cells, must be resolved before hiPS cells can be used clinically. The cell-sheet technique is one of the useful methods for transplanting large numbers of cells. We hypothesized that hiPS-CM-sheet transplantation would be feasible, safe, and therapeutically effective for the treatment of ischemic cardiomyopathy.
  
  
  RESULTS
  Human iPS cells were established by infecting human dermal fibroblasts with a retrovirus carrying Oct3/4, Sox2, Klf4, and c-Myc. Cardiomyogenic differentiation was induced by WNT signaling molecules, yielding hiPS-CMs that were almost 90% positive for α-actinin, Nkx2.5, and cardiac troponin T. hiPS-CM sheets were created using thermoresponsive dishes and transplanted over the myocardial infarcts in a porcine model of ischemic cardiomyopathy induced by ameroid constriction of the left anterior descending coronary artery (n=6 for the iPS group receiving sheet transplantation and the sham-operated group; both groups received tacrolimus daily). Transplantation significantly improved cardiac performance and attenuated left ventricular remodeling. hiPS-CMs were detectable 8 weeks after transplantation, but very few survived long term. No teratoma formation was observed in animals that received hiPS-CM sheets.
  
  
  CONCLUSIONS
  The culture system used yields a large number of highly pure hiPS-CMs, and hiPS-CM sheets could improve cardiac function after ischemic cardiomyopathy. This newly developed culture system and the hiPS-CM sheets may provide a basis for the clinical use of hiPS cells in cardiac regeneration therapy.
authors.affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawamura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Miki
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Satsuki
authors.initials: S
authors.lastname: Fukushima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Takuji
authors.initials: T
authors.lastname: Kawamura
authors.forename: Toru
authors.initials: T
authors.lastname: Kuratani
authors.forename: Takashi
authors.initials: T
authors.lastname: Daimon
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shimizu
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000295:instrumentation; D002454:Cell Differentiation / Q000187:drug effects; D015716:Electrocardiography, Ambulatory; D005240:Feasibility Studies; D005260:Female; D006085:Graft Survival; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000637:transplantation*; D000090062:Kruppel-Like Factor 4; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000637:transplantation*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D020127:Recovery of Function; D012190:Retroviridae / Q000235:genetics; D013552:Swine; D013556:Swine, Miniature; D013696:Temperature; D023822:Tissue Engineering / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014183:Transplantation, Heterologous; D014463:Ultrasonography; D051153:Wnt Proteins / Q000494:pharmacology
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051153:Wnt Proteins