A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity

Sergio Ruiz, Athanasia D. Panopoulos, Aída Herrerías, Karl Dimiter Bissig, Margaret Lutz, W. Travis Berggren, Inder M. Verma, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticlepeer-review

246 Scopus citations

Abstract

Human embryonic stem (hES) cells show an atypical cell-cycle regulation characterized by a high proliferation rate and a short G1 phase [1,2]. In fact, a shortened G1 phase might protect ES cells from external signals inducing differentiation, as shown for certain stem cells [3]. It has been suggested that self-renewal and pluripotency are intimately linked to cell-cycle regulation in ES cells [4-6], 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 [7-11]. 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.

Original languageEnglish (US)
Pages (from-to)45-52
Number of pages8
JournalCurrent Biology
Volume21
Issue number1
DOIs
StatePublished - Jan 11 2011
Externally publishedYes

Bibliographical note

Funding Information:
We especially thank Yasuhiko Kawakami, Jesús Paramio, Geoff Wahl, Chris Walsh, May Schwarz, Susie Camus, and Sergio Menendez for critically reading and improving the final version of the manuscript. We also express gratitude to Krystal Sousley for support at the Salk Institute Stem Cell Core, Kristen Brennand for assistance with reprogramming experiments, Mercè Marti for excellent work at the Center of Regenerative Medicine in Barcelona Histology and Bioimaging Department, and the rest of the Belmonte laboratory. S.R. was partially supported by the Instituto de Salud Carlos III (CGCV-1335/07-3). A.D.P. was partially supported by National Institutes of Health training grant T32 CA009370. Work in this manuscript was supported by grants from Fundació CELLEX, the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, and the Ministerio de Ciencia e Innovación.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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