Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells.
BACKGROUND
Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiac differentiation, yet their potential for heart disease therapy has not been tested.


RESULTS
In this study, fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC converted into an embryonic stem cell-like phenotype and demonstrated the ability to spontaneously assimilate into preimplantation host morula via diploid aggregation, unique to bona fide pluripotent cells. In utero, iPS-derived chimera executed differentiation programs to construct normal heart parenchyma patterning. Within infarcted hearts in the adult, intramyocardial delivery of iPS yielded progeny that properly engrafted without disrupting cytoarchitecture in immunocompetent recipients. In contrast to parental nonreparative fibroblasts, iPS treatment restored postischemic contractile performance, ventricular wall thickness, and electric stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue.


CONCLUSIONS
Fibroblasts reprogrammed by human stemness factors thus acquire the potential to repair acute myocardial infarction, establishing iPS in the treatment of heart disease.
Nelson
Timothy J
TJ
Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Martinez-Fernandez
Almudena
A
Yamada
Satsuki
S
Perez-Terzic
Carmen
C
Ikeda
Yasuhiro
Y
Terzic
Andre
A
D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000502:physiology; D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016259:Genes, myc; D005822:Genetic Vectors; D006321:Heart / Q000196:embryology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000502:physiology; D020127:Recovery of Function; D055748:SOXB1 Transcription Factors / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods*; D014161:Transduction, Genetic
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors