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.

METHODS AND 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: Masashi Kawamura, Shigeru Miyagawa, Kenji Miki, Atsuhiro Saito, Satsuki Fukushima, Takahiro Higuchi, Takuji Kawamura, Toru Kuratani, Takashi Daimon, Tatsuya Shimizu, Teruo Okano, Yoshiki Sawa
• Journal: Circulation (Circulation) Vol. 126 Issue 11 Suppl 1 Pg. S29-37 (Sep 11 2012) ISSN: 1524-4539 [Electronic] United States
• PMID: 22965990 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• KLF4 protein, human
• Kruppel-Like Factor 4
• Recombinant Fusion Proteins
• Transcription Factors
• Wnt Proteins

Topics

• Animals
• Cell Culture Techniques (instrumentation)
• Cell Differentiation (drug effects)
• Electrocardiography, Ambulatory
• Feasibility Studies
• Female
• Graft Survival
• Humans
• Induced Pluripotent Stem Cells (drug effects, transplantation)
• Kruppel-Like Factor 4
• Myocardial Infarction (diagnostic imaging, pathology, surgery)
• Myocytes, Cardiac (transplantation)
• Recombinant Fusion Proteins (genetics, physiology)
• Recovery of Function
• Retroviridae (genetics)
• Swine
• Swine, Miniature
• Temperature
• Tissue Engineering (methods)
• Transcription Factors (genetics, physiology)
• Transplantation, Heterologous
• Ultrasonography
• Wnt Proteins (pharmacology)