Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation |
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Authors: | Hee Jung Lim Jusong Kim Chang-Hwan Park Sang A. Lee Man Ryul Lee Kye-Seong Kim Jaesang Kim Yun Soo Bae |
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Affiliation: | From the ‡Department of Life Sciences, Ewha Womans University, Seoul 120-750, Korea.;the §Graduate School of Biomedical Science and Engineering, Department of Biomedical Science, Hanyang University, Seoul 133-791, Korea, and ;the ¶Soonchunhyang Institute of Medi-bioscience, Soon Chun Hyang University, Cheonan 31538, Korea |
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Abstract: | We have previously reported that Ahnak-mediated TGFβ signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak−/− MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak−/− MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak−/− MEF cells (Ahnak−/−-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak−/−-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak−/− MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation. |
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Keywords: | development differentiation embryonic stem cell induced pluripotent stem cell (iPS cell) (iPSC) Myc (c-Myc) |
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