Crucial Role of C-Myc in the Generation of Induced Pluripotent Stem Cells§

Authors


  • Author contributions: R.A.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, financial support; Y.H.: collection and assembly of data, and data analysis; M.U., M.N., C.T., M. Sunayama, S.A., M. Sugiura, and M.A.Y.: collection and assembly of data; Y.J.: collection and assembly of data, data analysis and interpretation; Y.K.: data analysis; M.A.: conception and design, financial support, manuscript writing, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS July 5, 2011.

Abstract

c-Myc transduction has been considered previously to be nonessential for induced pluripotent stem cell (iPSC) generation. In this study, we investigated the effects of c-Myc transduction on the generation of iPSCs from an inbred mouse strain using a genome integration-free vector to exclude the effects of the genetic background and the genomic integration of exogenous genes. Our findings reveal a clear difference between iPSCs generated using the four defined factors including c-Myc (4F-iPSCs) and those produced without c-Myc (3F-iPSCs). Molecular and cellular analyses did not reveal any differences between 3F-iPSCs and 4F-iPSCs, as reported previously. However, a chimeric mice formation test indicated clear differences, whereby few highly chimeric mice and no germline transmission was observed using 3F-iPSCs. Similar differences were also observed in the mouse line that has been widely used in iPSC studies. Furthermore, the defect in 3F-iPSCs was considerably improved by trichostatin A, a histone deacetyl transferase inhibitor, indicating that c-Myc plays a crucial role in iPSC generation through the control of histone acetylation. Indeed, low levels of histone acetylation were observed in 3F-iPSCs. Our results shed new light on iPSC generation mechanisms and strongly recommend c-Myc transduction for preparing high-quality iPSCs. STEM CELLS 2011; 29:1362–1370

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