Nanoscale Adhesive Architecture Coordinates With Matrix Stiffness to Regulate Stem Cell Aging via Focal Adhesion-Mediated Chromatin Remodeling and FOXO1 Activation.

Jiacheng Lei, Ruihao Xue, Qingqing Liang, Ge Yang, Xiaokai Pan, Tianxiang Ren, Kaikai Zheng, Qiang Wei, Ze Gong, Xiaojing Liu

State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Maxillofacial Plastic, Aesthetic and Trauma Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P. R. China. · pubmed

Paper

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.

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Research summary

The study demonstrates that nanoscale adhesive ligand spacing and matrix stiffness cooperatively regulate mesenchymal stem cell senescence through a mechanotransduction pathway involving focal adhesions, chromatin remodeling, and FOXO1 activation. This work provides mechanistic insight into how physical microenvironmental cues influence cellular aging, a fundamental process in regenerative medicine and tissue engineering, though it represents an incremental advance in understanding specific mechanobiological pathways rather than a breakthrough in lifespan extension.

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