title: A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity.
abstract: Human embryonic stem (hES) cells show an atypical cell-cycle regulation characterized by a high proliferation rate and a short G1 phase. In fact, a shortened G1 phase might protect ES cells from external signals inducing differentiation, as shown for certain stem cells. It has been suggested that self-renewal and pluripotency are intimately linked to cell-cycle regulation in ES cells, although little is known about the overall importance of the cell-cycle machinery in maintaining ES cell identity. An appealing model to address whether the acquisition of stem cell properties is linked to cell-cycle regulation emerged with the ability to generate induced pluripotent stem (iPS) cells by expression of defined transcription factors. Here, we show that the characteristic cell-cycle signature of hES cells is acquired as an early event in cell reprogramming. We demonstrate that induction of cell proliferation increases reprogramming efficiency, whereas cell-cycle arrest inhibits successful reprogramming. Furthermore, we show that cell-cycle arrest is sufficient to drive hES cells toward irreversible differentiation. Our results establish a link that intertwines the mechanisms of cell-cycle control with the mechanisms underlying the acquisition and maintenance of ES cell identity.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz
authors.forename: Athanasia D
authors.initials: AD
authors.lastname: Panopoulos
authors.forename: Aída
authors.initials: A
authors.lastname: Herrerías
authors.forename: Karl-Dimiter
authors.initials: KD
authors.lastname: Bissig
authors.forename: Margaret
authors.initials: M
authors.lastname: Lutz
authors.forename: W Travis
authors.initials: WT
authors.lastname: Berggren
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans