Interferon-γ-Induced Mesenchymal Stem Cell Exosomes Attenuate Chondrocyte Senescence and Osteoarthritis Progression by Hsp70.

Abstract

With the accelerating pace of population aging, the incidence of osteoarthritis (OA), a degenerative disease strongly associated with age, is rapidly increasing. Chondrocyte senescence is a major contributor to cartilage degeneration; however, effective therapeutic strategies targeting chondrocyte aging remain lacking. Mesenchymal stem cell (MSC)-based approaches have emerged as a promising means of combating cellular senescence, among which exosomes (Exos) play a pivotal role in mediating therapeutic effects. Compared with direct MSC transplantation, Exos offer a safer and more ethically acceptable alternative. Moreover, the functional properties of Exos can be modulated by the microenvironmental stimuli applied to MSCs, although the underlying molecular mechanisms remain largely unclear. In this study, we employed interferon-γ (IFN-γ) to precondition MSCs and generate functionally enhanced Exos (iExos). Both in vitro and in vivo experiments demonstrated that iExos exhibit superior antisenescent activity in chondrocytes and more effectively attenuate OA progression. Sequencing analysis, together with mechanistic studies, revealed that iExos exert these effects by sustaining mitochondrial AMPK-SIRT3 homeostasis in chondrocytes through Hsp70. These findings partially elucidate a key pathway by which stem cell-derived iExos combat chondrocyte senescence and may inform the design of stable, efficient, and safe MSC-based antisenescence strategies.