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

• Published in: Nature communications 2022-11, Vol.13 (1), p.6854-6854, Article 6854
• Main Authors: Zhang, Zheng, Sha, Baoyong, Zhao, Lingzhu, Zhang, Huan, Feng, Jinteng, Zhang, Cheng, Sun, Lin, Luo, Meiqing, Gao, Bin, Guo, Hui, Wang, Zheng, Xu, Feng, Lu, Tian Jian, Genin, Guy M., Lin, Min
• Format: Article
• Language: English
• Subjects: 13/100; 14/1; 14/19; 631/532/2074; 631/61/54/2295; 631/80/79/2066; 639/301/54/2295; Actin; Actin Depolymerizing Factors - metabolism; Adhesives - metabolism; Cadherins; Cadherins - metabolism; Cell culture; Cell Differentiation; Cell interactions; Cofilin; Deoxyribonucleic acid; Differentiation (biology); DNA; DNA - metabolism; Evolution; Extracellular matrix; Extracellular Matrix - metabolism; Fibers; Fibronectin; Humanities and Social Sciences; Humans; Hybridization; Integrins - metabolism; Localization; Mechanical stimuli; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Microenvironments; Mimicry; multidisciplinary; N-Cadherin; Osteogenesis; Peptides; Phosphorylation; Science; Science (multidisciplinary); Stem cells; Tissue engineering; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34424-0

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. Human mesenchymal stem cells differentiate in response to mechanical adhesive interactions in their microenvironment. Here, the authors develop a culture platform that can dynamically mimic the cell-cell and cell-extracellular matrix interactions associated with development and mesenchymal differentiation in vivo.