Nanoscale Adhesive Architecture Coordinates With Matrix Stiffness to Regulate Stem Cell Aging via Focal Adhesion‐Mediated Chromatin Remodeling and FOXO1 Activation
Abstract
ABSTRACT Stem cell aging critically limits the efficacy of regenerative biomaterials, yet how mechanical cues within the microenvironment modulate this process remains insufficiently understood. Here, we reveal that the nanoscale spacing of adhesive ligands imposes stiffness‐dependent effects on mesenchymal stem cell (MSC) senescence. Wider spacing (distance 150 nm) accelerates aging on stiff hydrogels (50 kPa) but mitigates it on soft hydrogels (5 kPa), relative to dense spacing (distance 30 nm). Using a molecular clutch‐based theoretical model, we demonstrate that ligand spacing and matrix stiffness cooperatively regulate cell behaviors through focal adhesion assembly. Enhanced focal adhesion formation amplifies stress fiber‐generated traction forces and nuclear envelope tension, leading to increased chromatin accessibility and transcriptional activation of FOXO1, a central regulator of cellular senescence. These mechanistic insights are further validated in vivo. Collectively, these findings delineate a mechanotransduction mechanism through which nanoscale adhesive architecture and matrix stiffness cooperatively govern stem cell aging.
Article Details
Authors (10)
Jiacheng Lei
Ruihao Xue
Chinese Academy of Sciences Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China
Qingqing Liang
Ge Yang
Xiaokai Pan
College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials and Engineering, Sichuan University
Tianxiang Ren
Department of Chemistry and Shenzhen Grubbs Institute, Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis
Kaikai Zheng
College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials and Engineering, Sichuan University
Qiang Wei
Shenzhen Geim Graphene Center, Shenzhen Key Laboratory of Advanced Layered Materials for Value-added Applications, Tsinghua-Berkeley Shenzhen Institute and Institute of Materials Research
Ze Gong
Chinese Academy of Sciences Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China
Xiaojing Liu
Department of Molecular and Structural Biochemistry