EpEX/EpCAM and Oct4 or Klf4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2α.
Epithelial cell adhesion molecule (EpCAM) was reported to be cleaved into extracellular domain of EpCAM (EpEX) and intracellular domain of EpCAM (EpICD). We previously reported that EpCAM serves as a potent stem cell marker which is highly and selectively expressed by undifferentiated rather than differentiated hESC. However, the functional role of EpCAM remains elusive. Here, we found that EpEX and EpCAM enhance the efficiency of OSKM reprogramming. Interestingly, Oct4 or Klf4 alone, but not Sox2, can successfully reprogram fibroblasts into iPSCs with EpEX and EpCAM. Moreover, EpEX and EpCAM trigger reprogramming via activation of STAT3, which leads to the nuclear-translocation of HIF2α. This study reveals the importance of a novel EpEX/EpCAM-STAT3-HIF2α signal in the reprogramming process, and uncovers a new means of triggering reprogramming by delivery of soluble and transmembrane proteins.
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.|Department of Life Science, National Taiwan University, Taipei, Taiwan.
I-I
II
Kuan
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Kang-Hao
KH
Liang
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.|School of Dentistry, National Taiwan University, Taipei, Taiwan.
Yi-Ping
YP
Wang
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.|Department of Clinical Medicine, School of Medicine, Zhejang University, Zhejiang, China.
Ting-Wen
TW
Kuo
Institute of Molecular Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Yaa-Jyuhn James
YJ
Meir
Institute of Molecular Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Sareina Chiung-Yuan
SC
Wu
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Shang-Chih
SC
Yang
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Jean
J
Lu
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Han-Chung
HC
Wu
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D000071858:Epithelial Cell Adhesion Molecule / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000071858:Epithelial Cell Adhesion Molecule; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D050796:STAT3 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C000715468:Klf4 protein, mouse; C494174:Pou5f1 protein, mouse