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Modeling Stem Cell Induction Processes

Author

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  • Filipe Grácio
  • Joaquim Cabral
  • Bruce Tidor

Abstract

Technology for converting human cells to pluripotent stem cell using induction processes has the potential to revolutionize regenerative medicine. However, the production of these so called iPS cells is still quite inefficient and may be dominated by stochastic effects. In this work we build mass-action models of the core regulatory elements controlling stem cell induction and maintenance. The models include not only the network of transcription factors NANOG, OCT4, SOX2, but also important epigenetic regulatory features of DNA methylation and histone modification. We show that the network topology reported in the literature is consistent with the observed experimental behavior of bistability and inducibility. Based on simulations of stem cell generation protocols, and in particular focusing on changes in epigenetic cellular states, we show that cooperative and independent reaction mechanisms have experimentally identifiable differences in the dynamics of reprogramming, and we analyze such differences and their biological basis. It had been argued that stochastic and elite models of stem cell generation represent distinct fundamental mechanisms. Work presented here suggests an alternative possibility that they represent differences in the amount of information we have about the distribution of cellular states before and during reprogramming protocols. We show further that unpredictability and variation in reprogramming decreases as the cell progresses along the induction process, and that identifiable groups of cells with elite-seeming behavior can come about by a stochastic process. Finally we show how different mechanisms and kinetic properties impact the prospects of improving the efficiency of iPS cell generation protocols.

Suggested Citation

  • Filipe Grácio & Joaquim Cabral & Bruce Tidor, 2013. "Modeling Stem Cell Induction Processes," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-17, May.
  • Handle: RePEc:plo:pone00:0060240
    DOI: 10.1371/journal.pone.0060240
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    References listed on IDEAS

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    1. Tarjei S. Mikkelsen & Jacob Hanna & Xiaolan Zhang & Manching Ku & Marius Wernig & Patrick Schorderet & Bradley E. Bernstein & Rudolf Jaenisch & Eric S. Lander & Alexander Meissner, 2008. "Dissecting direct reprogramming through integrative genomic analysis," Nature, Nature, vol. 454(7200), pages 49-55, July.
    2. Ryan Lister & Mattia Pelizzola & Yasuyuki S. Kida & R. David Hawkins & Joseph R. Nery & Gary Hon & Jessica Antosiewicz-Bourget & Ronan O’Malley & Rosa Castanon & Sarit Klugman & Michael Downes & Ruth , 2011. "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 68-73, March.
    3. Michael J. Boland & Jennifer L. Hazen & Kristopher L. Nazor & Alberto R. Rodriguez & Wesley Gifford & Greg Martin & Sergey Kupriyanov & Kristin K. Baldwin, 2009. "Adult mice generated from induced pluripotent stem cells," Nature, Nature, vol. 461(7260), pages 91-94, September.
    4. Siqin Bao & Fuchou Tang & Xihe Li & Katsuhiko Hayashi & Astrid Gillich & Kaiqin Lao & M. Azim Surani, 2009. "Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells," Nature, Nature, vol. 461(7268), pages 1292-1295, October.
    5. Jacob Hanna & Krishanu Saha & Bernardo Pando & Jeroen van Zon & Christopher J. Lengner & Menno P. Creyghton & Alexander van Oudenaarden & Rudolf Jaenisch, 2009. "Direct cell reprogramming is a stochastic process amenable to acceleration," Nature, Nature, vol. 462(7273), pages 595-601, December.
    6. Shinya Yamanaka, 2009. "Elite and stochastic models for induced pluripotent stem cell generation," Nature, Nature, vol. 460(7251), pages 49-52, July.
    7. Zhonghan Li & Tariq M. Rana, 2012. "A kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    8. Xiao-yang Zhao & Wei Li & Zhuo Lv & Lei Liu & Man Tong & Tang Hai & Jie Hao & Chang-long Guo & Qing-wen Ma & Liu Wang & Fanyi Zeng & Qi Zhou, 2009. "iPS cells produce viable mice through tetraploid complementation," Nature, Nature, vol. 461(7260), pages 86-90, September.
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