title: Divergent reprogramming routes lead to alternative stem-cell states.
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.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Tonge
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Corso
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Claudio
authors.initials: C
authors.lastname: Monetti
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Samer M I
authors.initials: SM
authors.lastname: Hussein
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Mira C
authors.initials: MC
authors.lastname: Puri
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Iacovos P
authors.initials: IP
authors.lastname: Michael
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Mira
authors.initials: M
authors.lastname: Li
authors.affiliation: 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Systems &Computational Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Mar
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Wood
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Maely E
authors.initials: ME
authors.lastname: Gauthier
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Othmar
authors.initials: O
authors.lastname: Korn
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Clancy
authors.affiliation: 1] Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia [2] Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), New South Wales 2010, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Preiss
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea [4] Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Wells
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Physiology, University of Toronto, Toronto, Ontario M5T 3H7, Canada [3] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Rogers
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada [3] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics* / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000145:classification / Q000166:cytology / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000145:classification / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D014157:Transcription Factors; D006655:Histone Deacetylases