title: Direct Induction of Trophoblast Stem Cells from Murine Fibroblasts.
abstract: Trophoblast stem cells (TSCs) arise from the first cell fate decision in the developing embryo and generate extra-embryonic lineages, giving rise to the fetal portion of the placenta. Mouse embryonic and extra-embryonic lineages are strictly separated by a distinct epigenetic barrier, which is not fully overcome following expression of TSC-determining factors in embryonic stem cells. Here, we show that transient expression of Tfap2c, Gata3, Eomes, and Ets2 is sufficient to reprogram mouse embryonic fibroblasts and post-natal tail-tip-derived fibroblasts into induced TSCs (iTSCs) and surmount the epigenetic barrier separating somatic from extra-embryonic lineages. iTSCs share nearly identical morphological characteristics, gene expression profiles, and DNA methylation patterns with blastocyst-derived TSCs. Furthermore, iTSCs display transgene-independent self-renewal, differentiate along extra-embryonic lineages, and chimerize host placentas following blastocyst injection. These findings provide insights into the transcription factor networks governing TSC identity and opportunities for studying the epigenetic barriers underlying embryonic and extra-embryonic lineage segregation.
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kubaczka
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Senner
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Cierlitza
authors.affiliation: Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kuckenberg
authors.affiliation: Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Peitz
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, 53127 Bonn, Germany. Electronic address: hubert.schorle@ukb.uni-bonn.de.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
mesh_terms: D000818:Animals; D002453:Cell Cycle; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology*; D051379:Mice; D014327:Trophoblasts / Q000166:cytology*