Modulating Glypican4 Suppresses Tumorigenicity of Embryonic Stem Cells While Preserving Self-Renewal and Pluripotency

Authors

  • Annalisa Fico,

    1. Institut de Biologie de Développement de Marseille-Luminy (IBDML), CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France
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  • Antoine De Chevigny,

    1. Institut de Biologie de Développement de Marseille-Luminy (IBDML), CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France
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    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

  • Joaquim Egea,

    1. IRBLLEIDA, Campus de Ciències de la Salut, Universitat de Lleida, C. de Montserrat Roig 2, Lleida, Spain
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    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

  • Michael R. Bösl,

    1. Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, Martinsried, Germany
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    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

  • Harold Cremer,

    1. Institut de Biologie de Développement de Marseille-Luminy (IBDML), CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France
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    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

  • Flavio Maina,

    1. Institut de Biologie de Développement de Marseille-Luminy (IBDML), CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France
    Search for more papers by this author
    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

  • Rosanna Dono

    Corresponding author
    1. Institut de Biologie de Développement de Marseille-Luminy (IBDML), CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France
    • IBDML, CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, 13288 Marseille Cedex 09, France
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    • Author contributions: A.F.: conception and design, collection, assembly of data, data analysis and interpretation, and final approval of the manuscript; A.D.C.: contribution to design and performed and interpreted the shRNA experiments in postnatal brains; J.E. and M.R.B.: contribution to design and performed and interpreted the chimeric mouse experiments; H.C.: contribution to conception and design of the shRNA experiments in postnatal brains and financial support; F.M.: contribution to experimental design, data interpretation, and financial support; R.D.: contribution to conception and design, data analysis and interpretation, provision of study materials, financial support, and manuscript writing.

    • Telephone: +33-4-91269266; Fax: +33-4-91820682


  • Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

Self-renewal and differentiation of stem cell depend on a dynamic interplay of cell-extrinsic and -intrinsic regulators. However, how stem cells perceive the right amount of signal and at the right time to undergo a precise developmental program remains poorly understood. The cell surface proteins Glypicans act as gatekeepers of environmental signals to modulate their perception by target cells. Here, we show that one of these, Glypican4 (Gpc4), is specifically required to maintain the self-renewal potential of mouse embryonic stem cells (ESCs) and to fine tune cell lineage commitment. Notably, Gpc4-mutant ESCs contribute to all embryonic cell lineages when injected in blastocyts but lose their intrinsic tumorigenic properties after implantation into nude mice. Therefore, our molecular and functional studies reveal that Gpc4 maintains distinct stemness features. Moreover, we provide evidence that self-renewal and lineage commitment of different stem cell types is fine tuned by Gpc4 activity by showing that Gpc4 is required for the maintenance of adult neural stem cell fate in vivo. Mechanistically, Gpc4 regulates self-renewal of ESCs by modulating Wnt/β-catenin signaling activities. Thus, our findings establish that Gpc4 acts at the interface of extrinsic and intrinsic signal regulation to fine tune stem cell fate. Moreover, the ability to uncouple pluripotent stem cell differentiation from tumorigenic potential makes Gpc4 as a promising target for cell-based regenerative therapies. Stem Cells2012;30:1863–1874

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