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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).
Kilian, Ka, Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).
McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483–495 (2004).
Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).
Head, B. P., Patel, H. H. & Insel, P. A. Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim. Biophys. Acta 1838, 532–545 (2014).
Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39 (2000).
Liu, A. P. & Fletcher, D. A. Actin polymerization serves as a membrane domain switch in model lipid bilayers. Biophys. J. 91, 4064–4070 (2006).
Gaus, K., Le Lay, S., Balasubramanian, N. & Schwartz, M. Integrin-mediated adhesion regulates membrane order. J. Cell Biol. 174, 725–734 (2006).
Head, B. P. et al. Microtubules and actin microfilaments regulate lipid raft/caveolae localization of adenylyl cyclase signaling components. J. Biol. Chem. 281, 26391–26399 (2006).
Lingwood, D. & Simons, K. Lipid rafts as a membrane-organizing principle. Science 327, 46–50 (2010).
Head, B. P. & Insel, P. A. Do caveolins regulate cells by actions outside of caveolae? Trends Cell Biol. 17, 51–57 (2007).
Palazzo, A. F., Eng, C. H., Schlaepfer, D. D., Marcantonio, E. E. & Gundersen, G. G. Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science 303, 836–839 (2004).
Kamiguchi, H. The region-specific activities of lipid rafts during axon growth and guidance. J. Neurochem. 98, 330–335 (2006).
Blank, N. et al. Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1. Immunol. Cell Biol. 85, 378–382 (2007).
Wüstner, D. Fluorescent sterols as tools in membrane biophysics and cell biology. Chem. Phys. Lipids 146, 1–25 (2007).
Parton, R. G. & Simons, K. The multiple faces of caveolae. Nat. Rev. Mol. Cell Biol. 8, 185–194 (2007).
Sezgin, E. et al. Elucidating membrane structure and protein behavior using giant plasma membrane vesicles. Nat. Protoc. 7, 1042–1051 (2012).
Gao, X. & Zhang, J. Spatiotemporal analysis of differential Akt regulation in plasma membrane microdomains. Mol. Biol. Cell 19, 4366–4373 (2008).
Lasserre, R. et al. Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. Nat. Chem. Biol. 4, 538–547 (2008).
Gao, X. et al. PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains. Proc. Natl Acad. Sci. USA 108, 14509–14514 (2011).
Calay, D. et al. Inhibition of Akt signaling by exclusion from lipid rafts in normal and transformed epidermal keratinocytes. J. Investigative Dermatol. 130, 1136–1145 (2010).
Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).
Schnitzer, J. E., Oh, P., Pinney, E. & Allard, J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J. Cell Biol. 127, 1217–1232 (1994).
Hirai, H. et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Therapeutics 9, 1956–1967 (2010).
Vanhaesebroeck, B., Stephens, L. & Hawkins, P. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13, 195–203 (2012).
Müller, P., Langenbach, A., Kaminski, A. & Rychly, J. Modulating the actin cytoskeleton affects mechanically induced signal transduction and differentiation in mesenchymal stem cells. PLoS ONE 8, 1–8 (2013).
Stevens, M. M. & George, J. H. Exploring and engineering the cell surface interface. Science 310, 1135–1138 (2005).
Place, E. S., Evans, N. D. & Stevens, M. M. Complexity in biomaterials for tissue engineering. Nat. Mater. 8, 457–470 (2009).
von Erlach, T. C., Hedegaard, M. A. B. & Stevens, M. M. High resolution Raman spectroscopy mapping of stem cell micropatterns. Analyst 140, 1798–1803 (2015).
Bertazzo, S., von Erlach, T., Goldoni, S., Çandarlıoğlu, P. L. & Stevens, M. M. Correlative light-ion microscopy for biological applications. Nanoscale 4, 2851–2854 (2012).
Tan, J. L., Liu, W., Nelson, C. M., Raghavan, S. & Chen, C. S. Simple approach to micropattern cells on common culture substrates by tuning substrate wettability. Tissue Eng. 10, 865–72 (2004).
Horejs, C. M. et al. Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information. Nat. Commun. 8, 1–15 (2017).
Leight, J. L., Wozniak, M. A., Chen, S., Lynch, M. L. & Chen, C. S. Matrix rigidity regulates a switch between TGF-1-induced apoptosis and epithelial-mesenchymal transition. Mol. Biol. Cell 23, 781–791 (2012).
Harris, A. R. & Charras, G. T. Experimental validation of atomic force microscopy-based cell elasticity measurements. Nanotechnology 22, 1–10 (2011).
Herrmann, I. K. et al. Differentiating sepsis from non-infectious systemic inflammation based on microvesicle-bacteria aggregation. Nanoscale 7, 13511–13520 (2015).
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).
The authors declare no competing financial interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Determination of Dielectric Properties of Cells using AC Electrokinetic-based Microfluidic Platform: A Review of Recent Advances
Modulation of the mechanosensing of mesenchymal stem cells by laser-induced patterning for the acceleration of tissue reconstruction through the Wnt/β-catenin signaling pathway activation
Acta Biomaterialia (2020)
Single‐cell high‐content imaging parameters predict functional phenotype of cultured human bone marrow stromal stem cells
STEM CELLS Translational Medicine (2020)
Improved Corrosion Fatigue and Immunomodulatory Osteogenesis of Hydrothermally Grown TiO <sub> 2</sub> Nanorods Coated SMATed-Titanium
SSRN Electronic Journal (2020)