title: Transient acquisition of pluripotency during somatic cell transdifferentiation with iPSC reprogramming factors.
abstract: Somatic cells can be transdifferentiated to other cell types without passing through a pluripotent state by ectopic expression of appropriate transcription factors. Recent reports have proposed an alternative transdifferentiation method in which fibroblasts are directly converted to various mature somatic cell types by brief expression of the induced pluripotent stem cell (iPSC) reprogramming factors Oct4, Sox2, Klf4 and c-Myc (OSKM) followed by cell expansion in media that promote lineage differentiation. Here we test this method using genetic lineage tracing for expression of endogenous Nanog and Oct4 and for X chromosome reactivation, as these events mark acquisition of pluripotency. We show that the vast majority of reprogrammed cardiomyocytes or neural stem cells obtained from mouse fibroblasts by OSKM-induced 'transdifferentiation' pass through a transient pluripotent state, and that their derivation is molecularly coupled to iPSC formation mechanisms. Our findings underscore the importance of defining trajectories during cell reprogramming by various methods.
authors.affiliation: 1] The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. [2] The Department of Gastroenterology, Rambam Health Care Campus &Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel.
authors.forename: Itay
authors.initials: I
authors.lastname: Maza
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Caspi
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Zviran
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Chomsky
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoach
authors.initials: Y
authors.lastname: Rais
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sergey
authors.initials: S
authors.lastname: Viukov
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Geula
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Buenrostro
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Leehee
authors.initials: L
authors.lastname: Weinberger
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Krupalnik
authors.affiliation: 1] The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. [2] The Department of Pediatrics and the Pediatric Immunology Unit, Rambam Health Care Campus &Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel.
authors.forename: Suhair
authors.initials: S
authors.lastname: Hanna
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Mirie
authors.initials: M
authors.lastname: Zerbib
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Dutton
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenleaf
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rada
authors.initials: R
authors.lastname: Massarwa
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Novershtern
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Jacob H
authors.identifier: 0000000320429974
authors.initials: JH
authors.lastname: Hanna
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation / Q000235:genetics*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D005260:Female; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors