Divergent reprogramming routes lead to alternative stem-cell states

Peter D. Tonge, Andrew J. Corso, Claudio Monetti, Samer M. I. Hussein, Mira C. Puri, Iacovos P. Michael, Mira Li, Dong-Sung Lee, Jessica C. Mar, Nicole Cloonan, David L. Wood, Maely E. Gauthier, Othmar Korn, Jennifer L. Clancy, Thomas Preiss, Sean M. Grimmond, Jong-Yeon Shin, Jeong-Sun Seo, Christine A. Wells, Ian M. Rogers and Andras Nagy ()
Additional contact information
Peter D. Tonge: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Andrew J. Corso: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Claudio Monetti: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Samer M. I. Hussein: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Mira C. Puri: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Iacovos P. Michael: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Mira Li: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Dong-Sung Lee: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
Jessica C. Mar: Albert Einstein College of Medicine of Yeshiva University
Nicole Cloonan: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
David L. Wood: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Maely E. Gauthier: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Othmar Korn: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Jennifer L. Clancy: The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia
Thomas Preiss: The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Jong-Yeon Shin: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
Jeong-Sun Seo: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
Christine A. Wells: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Ian M. Rogers: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Andras Nagy: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Nature, 2014, vol. 516, issue 7530, 192-197

Abstract: Abstract Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states.

Date: 2014
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DOI: 10.1038/nature14047

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