title: Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1.
abstract: Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One- and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4.
authors.affiliation: Laboratory of Cell Function Regulation, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.forename: June Seok
authors.initials: JS
authors.lastname: Heo
authors.forename: Jun Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Jun
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim
authors.forename: Jonggun
authors.initials: J
authors.lastname: Kim
authors.forename: Kwang Youn
authors.initials: KY
authors.lastname: Whang
authors.forename: Yong-Kook
authors.initials: YK
authors.lastname: Kang
authors.forename: Seungeun
authors.initials: S
authors.lastname: Yeo
authors.forename: Hee-Joung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Sejong
authors.initials: S
authors.lastname: Oh
authors.forename: Byung Sun
authors.initials: BS
authors.lastname: Yoon
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Seungkwon
authors.initials: S
authors.lastname: You
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology*; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C489421:Bmi1 protein, mouse; D053823:Hedgehog Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1