title: Extensive Nuclear Reprogramming Underlies Lineage Conversion into Functional Trophoblast Stem-like Cells.
abstract: Induced pluripotent stem cells (iPSCs) undergo extensive nuclear reprogramming and are generally indistinguishable from embryonic stem cells (ESCs) in their functional capacity and transcriptome and DNA methylation profiles. However, direct conversion of cells from one lineage to another often yields incompletely reprogrammed, functionally compromised cells, raising the question of whether pluripotency is required to achieve a high degree of nuclear reprogramming. Here, we show that transient expression of Gata3, Eomes, and Tfap2c in mouse fibroblasts induces stable, transgene-independent trophoblast stem-like cells (iTSCs). iTSCs possess transcriptional profiles highly similar to blastocyst-derived TSCs, with comparable methylation and H3K27ac patterns and genome-wide H2A.X deposition. iTSCs generate trophoectodermal lineages upon differentiation, form hemorrhagic lesions, and contribute to developing placentas in chimera assays, indicating a high degree of nuclear reprogramming, with no evidence of passage through a transient pluripotent state. Together, these data demonstrate that extensive nuclear reprogramming can be achieved independently of pluripotency.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Hana
authors.initials: H
authors.lastname: Benchetrit
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Herman
authors.affiliation: European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, AV Groningen 9713, the Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: van Wietmarschen
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University, New Haven, CT 06520, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Kirill
authors.initials: K
authors.lastname: Makedonski
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Maoz
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Nataly
authors.initials: N
authors.lastname: Yom Tov
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Danielle
authors.initials: D
authors.lastname: Stave
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lasry
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Valery
authors.initials: V
authors.lastname: Zayat
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University, New Haven, CT 06520, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Xiao
authors.affiliation: European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, AV Groningen 9713, the Netherlands; Skolkovo Institute of Science and Technology (Skoltech), Novaya str. 100, Skolkovo Moscow Region 143025, Russia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Sebban
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yossibug@ekmd.huji.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Buganim
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism