Reprogramming in vivo produces teratomas and iPS cells with totipotency features

Nature. 2013 Oct 17;502(7471):340-5. doi: 10.1038/nature12586. Epub 2013 Sep 11.

Abstract

Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming. By bone marrow transplantation, we demonstrate that haematopoietic cells can also be reprogrammed in vivo. Notably, reprogrammable mice present circulating iPS cells in the blood and, at the transcriptome level, these in vivo generated iPS cells are closer to embryonic stem cells (ES cells) than standard in vitro generated iPS cells. Moreover, in vivo iPS cells efficiently contribute to the trophectoderm lineage, suggesting that they achieve a more plastic or primitive state than ES cells. Finally, intraperitoneal injection of in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic markers. We conclude that reprogramming in vivo is feasible and confers totipotency features absent in standard iPS or ES cells. These discoveries could be relevant for future applications of reprogramming in regenerative medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Cells / cytology
  • Blood Cells / metabolism
  • Cell Dedifferentiation
  • Cell Separation
  • Cells, Cultured
  • Cellular Reprogramming* / genetics
  • Ectoderm / cytology
  • Embryoid Bodies / cytology
  • Embryoid Bodies / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Female
  • Fibroblasts / cytology
  • Gene Expression Profiling
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Intestines / cytology
  • Kidney / cytology
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Organ Specificity
  • Pancreas / cytology
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Stomach / cytology
  • Teratoma / genetics
  • Teratoma / metabolism*
  • Teratoma / pathology
  • Totipotent Stem Cells / cytology*
  • Totipotent Stem Cells / metabolism
  • Transcriptome / genetics
  • Trophoblasts / cytology

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse

Associated data

  • GEO/GSE48364