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(Circulation Research. 2009;105:648.)
© 2009 American Heart Association, Inc.

Cellular Biology

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 Perez-Terzic, Yasuhiro Ikeda, Andre Terzic

From the Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics (A.M.F., T.J.N., S.Y., S.R., A.E.A., C.P.T., A.T.), the Department of Physical Medicine and Rehabilitation (C.P.T.), and the Department of Molecular Medicine (Y.I.), Mayo Clinic, Rochester, Minn.

Correspondence to Andre Terzic, MD, PhD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail terzic.andre{at}mayo.edu

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, -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.

Key Words: induced pluripotent stem cells • chimera • cardiac • nuclear reprogramming

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On the Road to iPS Cell Cardiovascular Applications

Timothy J. Kamp and Gary E. Lyons
Circ. Res. 2009 105: 617-619. [Extract] [Full Text] [PDF]

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				T. J. Kamp and G. E. Lyons On the Road to iPS Cell Cardiovascular Applications Circ. Res., September 25, 2009; 105(7): 617 - 619. [Full Text] [PDF]