Cardiopoietic programming of embryonic stem cells for tumor-free heart repair.
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-alpha, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF-alpha 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-alpha-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.
Behfar
Atta
A
Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Perez-Terzic
Carmen
C
Faustino
Randolph S
RS
Arrell
D Kent
DK
Hodgson
Denice M
DM
Yamada
Satsuki
S
Puceat
Michel
M
Niederländer
Nicolas
N
Alekseev
Alexey E
AE
Zingman
Leonid V
LV
Terzic
Andre
A
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D032383:Myocytes, Cardiac / Q000166:cytology*; D009369:Neoplasms / Q000517:prevention & control; D012038:Regeneration / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017931:DNA Primers; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha