Programmable integrin and N-cadherin adhesive interactions modulate mechanosensing of mesenchymal stem cells by cofilin phosphorylation

Zheng Zhang, Baoyong Sha, Lingzhu Zhao, Huan Zhang, Jinteng Feng, Cheng Zhang, Lin Sun, Meiqing Luo, Bin Gao, Hui Guo, Zheng Wang, Feng Xu, Tian Jian Lu, Guy M. Genin and Min Lin ()
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Zheng Zhang: Xi’an Jiaotong University
Baoyong Sha: Xi’an Medical University
Lingzhu Zhao: Xi’an Jiaotong University
Huan Zhang: Xi’an Jiaotong University
Jinteng Feng: Xi’an Jiaotong University
Cheng Zhang: Xi’an Jiaotong University
Lin Sun: Xi’an Jiaotong University
Meiqing Luo: Xi’an Jiaotong University
Bin Gao: Second Affiliated Hospital of Air Force Military Medical University
Hui Guo: First Affiliated Hospital of Xi’an Jiaotong University
Zheng Wang: First Affiliated Hospital of Xi’an Jiaotong University
Feng Xu: Xi’an Jiaotong University
Tian Jian Lu: Nanjing University of Aeronautics and Astronautics
Guy M. Genin: Xi’an Jiaotong University
Min Lin: Xi’an Jiaotong University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract During mesenchymal development, the sources of mechanical forces transduced by cells transition over time from predominantly cell-cell interactions to predominantly cell-extracellular matrix (ECM) interactions. Transduction of the associated mechanical signals is critical for development, but how these signals converge to regulate human mesenchymal stem cells (hMSCs) mechanosensing is not fully understood, in part because time-evolving mechanical signals cannot readily be presented in vitro. Here, we established a DNA-driven cell culture platform that could be programmed to present the RGD peptide from fibronectin, mimicking cell-ECM interactions, and the HAVDI peptide from N-cadherin, mimicking cell-cell interactions, through DNA hybridization and toehold-mediated strand displacement reactions. The platform could be programmed to mimic the evolving cell-ECM and cell-cell interactions during mesenchymal development. We applied this platform to reveal that RGD/integrin ligation promoted cofilin phosphorylation, while HAVDI/N-cadherin ligation inhibited cofilin phosphorylation. Cofilin phosphorylation upregulated perinuclear apical actin fibers, which deformed the nucleus and thereby induced YAP nuclear localization in hMSCs, resulting in subsequent osteogenic differentiation. Our programmable culture platform is broadly applicable to the study of dynamic, integrated mechanobiological signals in development, healing, and tissue engineering.

Date: 2022
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DOI: 10.1038/s41467-022-34424-0

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