Cardiopoietic programming of embryonic stem cells for tumor-free heart repair

Atta Behfar, Carmen Perez-Terzic, Randolph S. Faustino, D. Kent Arrell, Denice M. Hodgson, Satsuki Yamada, Michel Puceat, Nicolas Niederländer, Alexey E. Alekseev, Leonid V. Zingman, Andre Terzic

Research output: Contribution to journalArticle

197 Scopus citations

Abstract

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-α, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF-α 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-α-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. JEM

Original languageEnglish (US)
Pages (from-to)405-420
Number of pages16
JournalJournal of Experimental Medicine
Volume204
Issue number2
DOIs
StatePublished - Feb 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Behfar, A., Perez-Terzic, C., Faustino, R. S., Arrell, D. K., Hodgson, D. M., Yamada, S., Puceat, M., Niederländer, N., Alekseev, A. E., Zingman, L. V., & Terzic, A. (2007). Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. Journal of Experimental Medicine, 204(2), 405-420. https://doi.org/10.1084/jem.20061916