Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm.
During mammalian embryonic development, the primitive streak initiates the differentiation of pluripotent epiblast cells into germ layers. Pluripotency can be reacquired in committed somatic cells using a combination of a handful of transcription factors, such as OCT3/4, SOX2, KLF4 and c-MYC (hereafter referred to as OSKM), albeit with low efficiency. Here we show that during OSKM-induced reprogramming towards pluripotency in human cells, intermediate cells transiently show gene expression profiles resembling mesendoderm, which is a major component of the primitive streak. Based on these findings, we discover that forkhead box H1 (FOXH1), a transcription factor required for anterior primitive streak specification during early development, significantly enhances the reprogramming efficiency of human fibroblasts by promoting their maturation, including mesenchymal to epithelial transition and the activation of late pluripotency markers. These results demonstrate that during the reprogramming process, human somatic cells go through a transient state that resembles mesendoderm.
1] Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2].
Kazutoshi
K
Takahashi
1] Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2].
Koji
K
Tanabe
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Mari
M
Ohnuki
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Megumi
M
Narita
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Aki
A
Sasaki
Development Unit, Gunma University Maebashi, Gunma 371-8511, Japan.
Masamichi
M
Yamamoto
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Michiko
M
Nakamura
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Kenta
K
Sutou
Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Kenji
K
Osafune
1] Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
Shinya
S
Yamanaka
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004707:Endoderm / Q000166:cytology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008648:Mesoderm / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000502:physiology
C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors