ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

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
  • Xinming Tong
    Xinming Tong
    Department of Orthopaedic Surgery, Stanford University, Stanford, California 94305, United States
    More by Xinming Tong
  • 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
Copyright © 2019 American Chemical Society

    Article Views





    Read OnlinePDF (4 MB)
    Supporting Info (1)»


    Abstract Image

    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.

    Supporting Information

    Jump To

    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)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 32 publications.

    1. Akram Abbasi, Sachiko Imaichi, Vincent Ling, Anita Shukla. Mesenchymal Stem Cell Behavior on Soft Hydrogels with Aligned Surface Topographies. ACS Applied Bio Materials 2022, 5 (5) , 1890-1900.
    2. Ruoxing Lei, Erin A. Akins, Kelly C. Y. Wong, Nicole A. Repina, Kayla J. Wolf, Garrett E. Dempsey, David V. Schaffer, Andreas Stahl, Sanjay Kumar. Multiwell Combinatorial Hydrogel Array for High-Throughput Analysis of Cell–ECM Interactions. ACS Biomaterials Science & Engineering 2021, 7 (6) , 2453-2465.
    3. Liangliang Yang, Lu Ge, Patrick van Rijn. Synergistic Effect of Cell-Derived Extracellular Matrices and Topography on Osteogenesis of Mesenchymal Stem Cells. ACS Applied Materials & Interfaces 2020, 12 (23) , 25591-25603.
    4. Bogdan Conrad, Camila Hayashi, Fan Yang. Gelatin-Based Microribbon Hydrogels Support Robust MSC Osteogenesis across a Broad Range of Stiffness. ACS Biomaterials Science & Engineering 2020, 6 (6) , 3454-3463.
    5. Jinxin Dou, Sifeng Mao, Haifang Li, Jin-Ming Lin. Combination Stiffness Gradient with Chemical Stimulation Directs Glioma Cell Migration on a Microfluidic Chip. Analytical Chemistry 2020, 92 (1) , 892-898.
    6. Aron N. Horvath, Claude N. Holenstein, Unai Silvan, Jess G. Snedeker. The Protein Mat(ters)—Revealing the Biologically Relevant Mechanical Contribution of Collagen- and Fibronectin-Coated Micropatterns. ACS Applied Materials & Interfaces 2019, 11 (44) , 41791-41798.
    7. Janine Grolleman, Nicole C. A. van Engeland, Minahil Raza, Sepinoud Azimi, Vito Conte, Cecilia M. Sahlgren, Carlijn V. C. Bouten. Environmental stiffness restores mechanical homeostasis in vimentin-depleted cells. Scientific Reports 2023, 13 (1)
    8. Yun-Ping Chen, Yue Shao, Peng-Cheng Chen, Kun Li, Jing-Yi Li, Jie Meng, Cheng-Lin Lv, Hao-Yu Liu, Cunjing Lv, Xi-Qiao Feng, Bo Li. Substrate nesting guides cyst morphogenesis of human pluripotent stem cells without 3D extracellular matrix overlay. Acta Biomaterialia 2023, 170 , 519-531.
    9. Xiangyi Wu, Haofang Zhu, Junyi Che, Ye Xu, Qian Tan, Yuanjin Zhao. Stem cell niche-inspired microcarriers with ADSCs encapsulation for diabetic wound treatment. Bioactive Materials 2023, 26 , 159-168.
    10. Zhenyin Chen, Yang Zou, Yonggang Lv. Dynamic-stiffening collagen-coated substrate enhances osteogenic differentiation of mesenchymal stem cells through integrin α2β1. Biomaterials Science 2023, 11 (13) , 4700-4712.
    11. Aylin Kara Özenler, Thomas Distler, Funda Tihminlioglu, Aldo R Boccaccini. Fish scale containing alginate dialdehyde-gelatin bioink for bone tissue engineering. Biofabrication 2023, 15 (2) , 025012.
    12. Masahiro Hakariya, Yoshinori Arisaka, Hiroki Masuda, Tetsuya Yoda, Takanori Iwata, Nobuhiko Yui. Suppressed Migration and Enhanced Cisplatin Chemosensitivity in Human Cancer Cell Lines by Tuning the Molecular Mobility of Supramolecular Biomaterials. Macromolecular Bioscience 2023, 23 (2)
    13. Xiaofei Li, Callie McLain, Michael S. Samuel, Michael F. Olson, Glenn L. Radice. Actomyosin-mediated cellular tension promotes Yap nuclear translocation and myocardial proliferation through α5 integrin signaling. Development 2023, 150 (2)
    14. Kshitiz Raj Shrestha, Do Hoon Lee, Woojae Chung, Seung-Wuk Lee, Byung Yang Lee, So Young Yoo. Biomimetic virus-based soft niche for ischemic diseases. Biomaterials 2022, 288 , 121747.
    15. Jennifer Flournoy, Shahad Ashkanani, Yun Chen. Mechanical regulation of signal transduction in angiogenesis. Frontiers in Cell and Developmental Biology 2022, 10
    16. Sungwoo Cho, Min Ju Shon, Boram Son, Gee Sung Eun, Tae-Young Yoon, Tai Hyun Park. Tension exerted on cells by magnetic nanoparticles regulates differentiation of human mesenchymal stem cells. Biomaterials Advances 2022, 139 , 213028.
    17. Haley Barnett, Mariya Shevchuk, Nicholas A. Peppas, Mary Caldorera-Moore. Influence of extracellular cues of hydrogel biomaterials on stem cell fate. Journal of Biomaterials Science, Polymer Edition 2022, 33 (10) , 1324-1347.
    18. Alessandro Gandin, Veronica Torresan, Lorenzo Ulliana, Tito Panciera, Paolo Contessotto, Anna Citron, Francesca Zanconato, Michelangelo Cordenonsi, Stefano Piccolo, Giovanna Brusatin. Broadly Applicable Hydrogel Fabrication Procedures Guided by YAP/TAZ‐Activity Reveal Stiffness, Adhesiveness, and Nuclear Projected Area as Checkpoints for Mechanosensing. Advanced Healthcare Materials 2022, 11 (3)
    19. Tianyi Luo, Bowen Tan, Lengjing Zhu, Yating Wang, Jinfeng Liao. A Review on the Design of Hydrogels With Different Stiffness and Their Effects on Tissue Repair. Frontiers in Bioengineering and Biotechnology 2022, 10
    20. Chiara Camillo, Nicola Facchinello, Giulia Villari, Giulia Mana, Noemi Gioelli, Chiara Sandri, Matteo Astone, Dora Tortarolo, Fabiana Clapero, Dafne Gays, Roxana E. Oberkersch, Marco Arese, Luca Tamagnone, Donatella Valdembri, Massimo M. Santoro, Guido Serini. LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion. Journal of Cell Biology 2021, 220 (11)
    21. Badri Narayanan Narasimhan, Matthew S. Horrocks, Jenny Malmström. Hydrogels with Tunable Physical Cues and Their Emerging Roles in Studies of Cellular Mechanotransduction. Advanced NanoBiomed Research 2021, 1 (10)
    22. Jason S. Silver, K. Arda Günay, Alicia A. Cutler, Thomas O. Vogler, Tobin E. Brown, Bradley T. Pawlikowski, Olivia J. Bednarski, Kendra L. Bannister, Cameron J. Rogowski, Austin G. Mckay, Frank W. DelRio, Bradley B. Olwin, Kristi S. Anseth. Injury-mediated stiffening persistently activates muscle stem cells through YAP and TAZ mechanotransduction. Science Advances 2021, 7 (11)
    23. Ting Su, Mengying Zhang, Qiankun Zeng, Wenhao Pan, Yijing Huang, Yuna Qian, Wei Dong, Xiaoliang Qi, Jianliang Shen. Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering. Bioactive Materials 2021, 6 (3) , 579-588.
    24. George Flamourakis, Antonis Kordas, Georgios D. Barmparis, Anthi Ranella, Maria Farsari. Low-autofluorescence, transparent composite for multiphoton 3D printing. Optical Materials Express 2021, 11 (3) , 801.
    25. Man Zhang, Qian Sun, Yiling Liu, Zhiqin Chu, Leixiao Yu, Yong Hou, Heemin Kang, Qiang Wei, Weifeng Zhao, Joachim P. Spatz, Changsheng Zhao, Elisabetta A. Cavalcanti-Adam. Controllable ligand spacing stimulates cellular mechanotransduction and promotes stem cell osteogenic differentiation on soft hydrogels. Biomaterials 2021, 268 , 120543.
    26. Xuliang Ma, Chao Wang, Yunmeng Da, Ruiqing Cheng, Jingjing Zhang, Xiaotong Qiao. Expressions of Yes-associated Protein and Transcriptional Co-Activator with PDZ-binding Motif during the Development of Mandibular First Molar in BALB/c Mice. Journal of Hard Tissue Biology 2021, 30 (2) , 145-150.
    27. Suqiong Zhou, Yuanwei Pan, Jianguang Zhang, Yan Li, Falko Neumann, Tanja Schwerdtle, Wenzhong Li, Rainer Haag. Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells. Nanoscale 2020, 12 (47) , 24006-24019.
    28. Anthony A. Bertrand, Sri Harshini Malapati, Dean T. Yamaguchi, Justine C. Lee. The Intersection of Mechanotransduction and Regenerative Osteogenic Materials. Advanced Healthcare Materials 2020, 9 (20)
    29. Xinqi Huang, Xiner Xiong, Jun Liu, Zhihe Zhao, Xiao Cen. MicroRNAs-containing extracellular vesicles in bone remodeling: An emerging frontier. Life Sciences 2020, 254 , 117809.
    30. Hannah K. Vanyai, Fabrice Prin, Oriane Guillermin, Bishara Marzook, Stefan Boeing, Alexander Howson, Rebecca E. Saunders, Thomas Snoeks, Michael Howell, Timothy J. Mohun, Barry Thompson. Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway. Development 2020, 16
    31. Alice E. Stanton, Xinming Tong, Fan Yang. Extracellular matrix type modulates mechanotransduction of stem cells. Acta Biomaterialia 2019, 96 , 310-320.
    32. Alice E. Stanton, Xinming Tong, Fan Yang. Varying solvent type modulates collagen coating and stem cell mechanotransduction on hydrogel substrates. APL Bioengineering 2019, 3 (3)

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect