title: Nuclear reprogramming with c-Myc potentiates glycolytic capacity of derived induced pluripotent stem cells.
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.
authors.affiliation: 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.
authors.forename: Clifford D L
authors.initials: CD
authors.lastname: Folmes
authors.forename: Almudena
authors.initials: A
authors.lastname: Martinez-Fernandez
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Faustino
authors.forename: Satsuki
authors.initials: S
authors.lastname: Yamada
authors.forename: Carmen
authors.initials: C
authors.lastname: Perez-Terzic
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nelson
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D065150:Cellular Reprogramming; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000187:drug effects; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D015415:Biomarkers; D016271:Proto-Oncogene Proteins c-myc