Stiff Extracellular Matrix Rejuvenates Aged Mesenchymal Stem Cells via PI3K‐AKT Signaling

Mesenchymal stem cells (MSCs) are widely used to modulate immune responses and promote tissue regeneration, but cellular senescence significantly impairs their therapeutic potential. MSCs undergo senescence characterized by an enlarged morphology, reduced proliferative capacity, and altered expression of genes related to the cytoskeleton. This study revealed that the mechanical microenvironment critically regulates MSC aging. Culturing senescent MSCs on high-stiffness extracellular matrix (ECM) hydrogels reverses key aspects of the senescent phenotype, including the restoration of normal morphology, improved cytoskeletal integrity, and enhanced proliferation. This mechanical rescue is accompanied by genetic reprogramming and activation of the PI3K-AKT signaling pathway. The inhibition of PI3K-Akt with LY294002 abolished these rejuvenating effects. These findings demonstrate that the mechanical microenvironment can reprogram senescent MSCs through PI3K-AKT-mediated mechanotransduction, offering a novel strategy to restore stem cell function in aging and regenerative medicine.