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

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.

Frizzled-9 activates YAP to rescue simulated microgravity induced osteoblasts dysfunction

“…YAP is a mechanosensitive transcriptional regulator with a major role in differentiation (Zhang et al, 2022). To investigate the underlying mechanism of Fzd9 under SMG, we further studied YAP which was associated with osteogenesis.…”

Frizzled‐9 triggers actin polymerization and activates mechano‐transducer YAP to rescue simulated microgravity‐induced osteoblast dysfunction

“…19 YAP is a mechanosensitive transcriptional regulator with a major role in differentiation. 41 To elucidate the underlying mechanism of Fzd9 under SMG induction, we further studied osteogenesis-associated YAP and elucidated the mechanism underlying SMG-induced osteoblast dysfunction. We observed that the nuclear localization of YAP was significantly inhibited due to 1-3 days of SMG induction.…”

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair

“…[21][22][23] Endogenous components of the ECM, such as fibronectin, are, along with integrins, the main recognition molecules for cell adhesion. [24] Fibronectin is usually glycosylated and contains a cell adhesion sequence (arginine-glycine-aspartic acid [RGD]), which can promote cell-substratum detachment and cell-cell adhesion by binding to integrins. [25,26] ECM proteins that regulate cell morphogenesis and cell-cell interactions contain RGD sequences that are usually glycosylated.…”