Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2.
Ectopic expression of defined sets of genetic factors can reprogram somatic cells to induced pluripotent stem (iPS) cells that closely resemble embryonic stem (ES) cells. The low efficiency with which iPS cells are derived hinders studies on the molecular mechanism of reprogramming, and integration of viral transgenes, in particular the oncogenes c-Myc and Klf4, may handicap this method for human therapeutic applications. Here we report that valproic acid (VPA), a histone deacetylase inhibitor, enables reprogramming of primary human fibroblasts with only two factors, Oct4 and Sox2, without the need for the oncogenes c-Myc or Klf4. The two factor-induced human iPS cells resemble human ES cells in pluripotency, global gene expression profiles and epigenetic states. These results support the possibility of reprogramming through purely chemical means, which would make therapeutic use of reprogrammed cells safer and more practical.
Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Danwei
D
Huangfu
Kenji
K
Osafune
René
R
Maehr
Wenjun
W
Guo
Astrid
A
Eijkelenboom
Shuibing
S
Chen
Whitney
W
Muhlestein
Douglas A
DA
Melton
D000818:Animals; D001709:Biotechnology / Q000379:methods; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects; D003470:Culture Media; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D003470:Culture Media; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014635:Valproic Acid