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Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Department of Medical Genetics, and Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905

CORRESPONDENCE Andre Terzic: terzic.andre{at}mayo.edu

Embryonic stem cells have the distinct potential for tissue regeneration, including cardiac repair. Their propensity for multilineage differentiation carries, however, the liability of neoplastic growth, impeding therapeutic application. Here, the tumorigenic threat associated with embryonic stem cell transplantation was suppressed by cardiac-restricted transgenic expression of the reprogramming cytokine TNF-, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF- to promote cardiac differentiation was recapitulated in embryoid bodies in vitro. The procardiogenic action required an intact endoderm and was mediated by secreted cardio-inductive signals. Resolved TNF-–induced endoderm-derived factors, combined in a cocktail, secured guided differentiation of embryonic stem cells in monolayers produce cardiac progenitors termed cardiopoietic cells. Characterized by a down-regulation of oncogenic markers, up-regulation, and nuclear translocation of cardiac transcription factors, this predetermined population yielded functional cardiomyocyte progeny. Recruited cardiopoietic cells delivered in infarcted hearts generated cardiomyocytes that proliferated into scar tissue, integrating with host myocardium for tumor-free repair. Thus, cardiopoietic programming establishes a strategy to hone stem cell pluripotency, offering a tumor-resistant approach for regeneration.

Abbreviations used: BMP, bone morphogenetic protein; CFP, cyan fluorescence protein; EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; MEF, myocyte enhancer factor; NGF, nerve growth factor; TACE, TNF- converting enzyme; TAK, TGF-ß–activated kinase; VEGF, vascular endothelial growth factor.

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