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Nuclear Reprogramming with c-Myc Potentiates Glycolytic Capacity of Derived Induced Pluripotent Stem Cells

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Abstract

Reprogramming strategies influence the differentiation capacity of derived induced pluripotent stem (iPS) cells. Removal of the reprogramming factor c-Myc reduces tumorigenic incidence and increases cardiogenic potential of iPS cells. c-Myc is a regulator of energy metabolism, yet the impact on metabolic reprogramming underlying pluripotent induction is unknown. Here, mitochondrial and metabolic interrogation of iPS cells derived with (4F) and without (3F) c-Myc demonstrated that nuclear reprogramming consistently reverted mitochondria to embryonic-like immature structures. Metabolomic profiling segregated derived iPS cells from the parental somatic source based on the attained pluripotency-associated glycolytic phenotype and discriminated between 3F versus 4F clones based upon glycolytic intermediates. Real-time flux analysis demonstrated a greater glycolytic capacity in 4F iPS cells, in the setting of equivalent oxidative capacity to 3F iPS cells. Thus, inclusion of c-Myc potentiates the pluripotent glycolytic behavior of derived iPS cells, supporting c-Myc-free reprogramming as a strategy to facilitate oxidative metabolism-dependent lineage engagement.

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Acknowledgments

This work was supported by the National Institutes of Health, Canadian Institutes of Health Research, American Heart Association, Fondation Leducq, Marriott Foundation, and Mayo Clinic Center for Regenerative Medicine.

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  1. Center for Regenerative Medicine and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology & Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA

    Clifford D. L. Folmes, Almudena Martinez-Fernandez, Randolph S. Faustino, Satsuki Yamada, Carmen Perez-Terzic, Timothy J. Nelson & Andre Terzic

  2. Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Andre Terzic

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  1. Clifford D. L. Folmes
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  2. Almudena Martinez-Fernandez
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Correspondence to Andre Terzic.

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Folmes, C.D.L., Martinez-Fernandez, A., Faustino, R.S. et al. Nuclear Reprogramming with c-Myc Potentiates Glycolytic Capacity of Derived Induced Pluripotent Stem Cells. J. of Cardiovasc. Trans. Res. 6, 10–21 (2013). https://doi.org/10.1007/s12265-012-9431-2

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