Stimulus-triggered fate conversion of somatic cells into pluripotency.
Here we report a unique cellular reprogramming phenomenon, called stimulus-triggered acquisition of pluripotency (STAP), which requires neither nuclear transfer nor the introduction of transcription factors. In STAP, strong external stimuli such as a transient low-pH stressor reprogrammed mammalian somatic cells, resulting in the generation of pluripotent cells. Through real-time imaging of STAP cells derived from purified lymphocytes, as well as gene rearrangement analysis, we found that committed somatic cells give rise to STAP cells by reprogramming rather than selection. STAP cells showed a substantial decrease in DNA methylation in the regulatory regions of pluripotency marker genes. Blastocyst injection showed that STAP cells efficiently contribute to chimaeric embryos and to offspring via germline transmission. We also demonstrate the derivation of robustly expandable pluripotent cell lines from STAP cells. Thus, our findings indicate that epigenetic fate determination of mammalian cells can be markedly converted in a context-dependent manner by strong environmental cues.
1] Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Laboratory for Cellular Reprogramming, RIKEN Center for Developmental biology, Kobe 650-0047, Japan [3] Laboratory for Genomic Reprogramming, RIKEN Center for Developmental biology, Kobe 650-0047, Japan.
Haruko
H
Obokata
1] Laboratory for Genomic Reprogramming, RIKEN Center for Developmental biology, Kobe 650-0047, Japan [2] Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan.
Teruhiko
T
Wakayama
Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental biology, Kobe 650-0047, Japan.
Yoshiki
Y
Sasai
Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Koji
K
Kojima
1] Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Pathology, Irwin Army Community Hospital, Fort Riley, Kansas 66442, USA.
Martin P
MP
Vacanti
Laboratory for Pluripotent Stem Cell Studies, RIKEN Center for Developmental biology, Kobe 650-0047, Japan.
Hitoshi
H
Niwa
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
Masayuki
M
Yamato
Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Charles A
CA
Vacanti
D000143:Acids / Q000494:pharmacology*; D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000187:drug effects*; D002678:Chimera / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D009928:Organ Specificity
D000143:Acids; D050814:Octamer Transcription Factor-3; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse