N-cadherin mediates replicative senescence of mesenchymal stem cells via regulation of intercellular adhesion

Human mesenchymal stem cells (hMSCs) undergo progressive functional decline during long-term ex vivo expansion, which limits their therapeutic potential. However, the contribution of intercellular adhesion to this process remains unclear. By comparing hMSCs at different passage stages, we found that replicative senescence is accompanied by impaired collective motility homeostasis in near-confluent monolayers, diminished traction forces and altered monolayer stress distribution, concomitant with upregulated N-cadherin expression. Notably, N-cadherin knockdown or pharmacological blockade of its homophilic binding using ADH-1 restored migratory dynamics, enhanced traction generation and alleviated senescence-associated phenotypes. These findings identify N-cadherin as a crucial regulator of replicative senescence and highlight intercellular adhesion as a potential target for delaying senescence during ex vivo stem cell expansion.