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Biochemical Ligand Density Regulates Yes-Associated Protein Translocation in Stem Cells through Cytoskeletal Tension and Integrins

  • Alice E. Stanton
    Alice E. Stanton
    Department of Bioengineering, Stanford University, Stanford, California 94305, United States
    More by Alice E. Stanton
    Orcidhttp://orcid.org/0000-0002-8981-0629
  • , 
  • Xinming Tong
    Xinming Tong
    Department of Orthopaedic Surgery, Stanford University, Stanford, California 94305, United States
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  • , 
  • Soah Lee
    Soah Lee
    Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, United States
    More by Soah Lee
  • , and 
  • Fan Yang*
    Fan Yang
    Department of Bioengineering  and  Department of Orthopaedic Surgery, Stanford University, Stanford, California 94305, United States
    *E-mail: [email protected]. Phone: 650-725-7128. Fax: 650-723-9370.
    More by Fan Yang
Cite this: ACS Appl. Mater. Interfaces 2019, 11, 9, 8849–8857
Publication Date (Web):February 21, 2019
https://doi.org/10.1021/acsami.8b21270
Copyright © 2019 American Chemical Society
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    Abstract

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    Different tissue types are characterized by varying stiffness and biochemical ligands. Increasing substrate stiffness has been shown to trigger Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet the role of ligand density in modulating mechanotransduction and stem cell fate remains largely unexplored. Using polyacrylamide hydrogels coated with fibronectin as a model platform, we showed that stiffness-induced YAP translocation occurs only at intermediate ligand densities. At low or high ligand densities, YAP localization is dominated by ligand density independent of substrate stiffness. We further showed that ligand density-induced YAP translocation requires cytoskeleton tension and αVβ3-integrin binding. Finally, we demonstrate that increasing ligand density alone can enhance osteogenic differentiation regardless of matrix stiffness. Together, the findings from the present study establish ligand density as an important parameter for modulating stem cell mechanotransduction and differentiation, which is mediated by integrin clustering, focal adhesion, and cytoskeletal tension.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b21270.

    • Density effect of RGD-peptide on YAP translocation, methods of YAP and F-actin quantification, further confocal analysis of conditions, and RT-PCR analysis of osteogenic study (PDF)

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