IPS programmed without c-MYC yield proficient cardiogenesis for functional heart chimerism

Almudena Martinez-Fernandez, Timothy J Nelson, Satsuki Yamada, Santiago Reyes, Alexey E. Alekseev, Carmen M Terzic, Yasuhiro H Ikeda, Andre Terzic

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

RATIONALE:: Induced pluripotent stem cells (iPS) allow derivation of pluripotent progenitors from somatic sources. Originally, iPS were induced by a stemness-related gene set that included the c-MYC oncogene. OBJECTIVE:: Here, we determined from embryo to adult the cardiogenic proficiency of iPS programmed without c-MYC, a cardiogenicity-associated transcription factor. METHODS AND RESULTS:: Transgenic expression of 3 human stemness factors SOX2, OCT4, and KLF4 here reset murine fibroblasts to the pluripotent ground state. Transduction without c-MYC reversed cellular ultrastructure into a primitive archetype and induced stem cell markers generating 3-germ layers, all qualifiers of acquired pluripotency. Three-factor induced iPS (3F-iPS) clones reproducibly demonstrated cardiac differentiation properties characterized by vigorous beating activity of embryoid bodies and robust expression of cardiac Mef2c, α-actinin, connexin43, MLC2a, and troponin I. In vitro isolated iPS-derived cardiomyocytes demonstrated functional excitation-contraction coupling. Chimerism with 3F-iPS derived by morula-stage diploid aggregation was sustained during prenatal heart organogenesis and contributed in vivo to normal cardiac structure and overall performance in adult tumor-free offspring. CONCLUSIONS:: Thus, 3F-iPS bioengineered without c-MYC achieve highest stringency criteria for bona fide cardiogenesis enabling reprogrammed fibroblasts to yield de novo heart tissue compatible with native counterpart throughout embryological development and into adulthood.

Original languageEnglish (US)
Pages (from-to)648-656
Number of pages9
JournalCirculation Research
Volume105
Issue number7
DOIs
StatePublished - Sep 2009

Fingerprint

Induced Pluripotent Stem Cells
Chimerism
Fibroblasts
Embryoid Bodies
Actinin
Morula
Germ Layers
Excitation Contraction Coupling
Connexin 43
Troponin I
Organogenesis
Diploidy
Oncogenes
Cardiac Myocytes
Transcription Factors
Stem Cells
Embryonic Structures
Clone Cells

Keywords

  • Cardiac
  • Chimera
  • Induced pluripotent stem cells
  • Nuclear reprogramming

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

IPS programmed without c-MYC yield proficient cardiogenesis for functional heart chimerism. / Martinez-Fernandez, Almudena; Nelson, Timothy J; Yamada, Satsuki; Reyes, Santiago; Alekseev, Alexey E.; Terzic, Carmen M; Ikeda, Yasuhiro H; Terzic, Andre.

In: Circulation Research, Vol. 105, No. 7, 09.2009, p. 648-656.

Research output: Contribution to journalArticle

Martinez-Fernandez, Almudena ; Nelson, Timothy J ; Yamada, Satsuki ; Reyes, Santiago ; Alekseev, Alexey E. ; Terzic, Carmen M ; Ikeda, Yasuhiro H ; Terzic, Andre. / IPS programmed without c-MYC yield proficient cardiogenesis for functional heart chimerism. In: Circulation Research. 2009 ; Vol. 105, No. 7. pp. 648-656.
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AU - Nelson, Timothy J

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AU - Reyes, Santiago

AU - Alekseev, Alexey E.

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AU - Ikeda, Yasuhiro H

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