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Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate

Nature Materials volume 17, pages 237–242 (2018)Cite this article

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Abstract

Cell size and shape affect cellular processes such as cell survival, growth and differentiation1,2,3,4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications.

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Fig. 1: Cell geometry induces changes in cytoskeletal arrangement and cell contractility.
Fig. 2: Cell geometry regulates plasma membrane morphology and topography.
Fig. 3: Signal intensity of lipid raft markers is dependent on cell geometry.
Fig. 4: Akt recruitment to the plasma membrane and activation are dependent on cell geometry.
Fig. 5: Lipid rafts and Akt signalling mediate cell-geometry-dependent hMSC differentiation.

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Acknowledgements

We thank H. M. Textor and F. Anderegg (ETH Zurich) for providing silicon masters for micro-contact printing as well as S. Rothery for training and guidance regarding TIRF microscopy (FILM facility at Imperial College London). T.C.v.E. was supported by an EPSRC DTA PhD award. S.B. was supported by the Rosetrees Trust and the Stoneygate Trust and the Junior Research Fellowship scheme at Imperial College London. M.M.S. gratefully acknowledges ERC starting grant “Naturale” for funding (206807), Wellcome Trust Senior Investigator Award (098411/Z/12/Z) and the Rosetrees Trust. A.D.R.H. gratefully acknowledges ERC starting grant "ForceRegulation' (282051).

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Authors and Affiliations

  1. Department of Materials, Imperial College London, London, UK

    Thomas C. von Erlach, Sergio Bertazzo, Christine-Maria Horejs, Stephanie A. Maynard, Hélène Autefage, Charalambos Kallepitis, Armando del Río Hernández, Silvia Goldoni & Molly M. Stevens

  2. Department of Bioengineering, Imperial College London, London, UK

    Thomas C. von Erlach, Christine-Maria Horejs, Stephanie A. Maynard, Simon Attwood, Benjamin K. Robinson, Hélène Autefage, Charalambos Kallepitis, Silvia Goldoni & Molly M. Stevens

  3. Institute of Biomedical Engineering, Imperial College London, London, UK

    Thomas C. von Erlach, Christine-Maria Horejs, Stephanie A. Maynard, Hélène Autefage, Charalambos Kallepitis, Silvia Goldoni & Molly M. Stevens

  4. Department of Medical Physics & Biomedical Engineering, University College London, London, UK

    Sergio Bertazzo

  5. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Michele A. Wozniak & Christopher S. Chen

  6. Department of Bioengineering and the Biological Design Center, Boston University, Boston, MA, USA

    Christopher S. Chen

  7. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Christopher S. Chen

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  1. Thomas C. von Erlach
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Contributions

T.C.v.E. designed experiments, developed the substrates and conducted experiments, analysed and interpreted the data and wrote the manuscript. S.B. designed and carried out ion and electron microscopy experiments and analysed the data. M.A.W. conducted viral transfection experiments and revised the manuscript. C.K. performed 3D plasma membrane reconstruction and analysis. B.K.R. and S.A. conducted AFM measurements. C.-M.H. carried out western blots. C.S.C. revised the manuscript and consulted in experimental design. A.D.R.H. revised the manuscript and supervised S.A. H.A. helped with hMSC cultivation and differentiation experiments and revised the manuscript. S.A.M. helped with cell micropattern preparations and revised the manuscript. S.G. supervised the project, helped in experimental design, data analysis and interpretation, and co-wrote the manuscript. M.M.S. supervised the project, co-wrote the manuscript and helped in experimental design and data interpretation.

Corresponding authors

Correspondence to Silvia Goldoni or Molly M. Stevens.

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von Erlach, T.C., Bertazzo, S., Wozniak, M.A. et al. Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate. Nature Mater 17, 237–242 (2018). https://doi.org/10.1038/s41563-017-0014-0

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