Mesenchymal stem cell senescence: Mechanisms and rejuvenation strategies

Abstract

Cellular senescence is a key contributor to organismal ageing and reduces the regenerative capacity of mesenchymal stem cells (MSCs), limiting their therapeutic potential in treating age-related diseases. This thesis aimed to investigate the mechanisms and functional consequences of MSC senescence and to develop strategies to rejuvenate senescent cells. Using adipose-derived mesenchymal stem cells (ASCs), this study first examined the effects of the chemotherapeutic drug doxorubicin (DOX) on senescence. Both short- and long-term DOX exposure induced senescence; however, while long-term exposure impaired osteogenic differentiation, short-term exposure enhanced osteogenesis. Transcriptomic analysis identified insulin-like growth factor 2 (IGF2) as a potential regulator of this dual effect, and IGF2 treatment restored osteogenic potential in senescent ASCs, suggesting a beneficial role of transient stress-induced senescence. To explore rejuvenation strategies, this thesis investigated both biomaterial and drug delivery approaches. Osteopontin (OPN), a major extracellular matrix protein, was shown to reverse senescence-associated phenotypes in replicative senescent ASCs, restoring proliferation, osteogenic differentiation, trophic support, and regulating cell morphology. In parallel, a liposome-based drug delivery system was developed to encapsulate nicotinamide mononucleotide (NMN), an anti-senescence drug. Optimised formulations achieved high encapsulation efficiency and reduced the expression of senescence markers in vitro. Together, these findings advance understanding of MSC senescence and identify OPN-based biomaterials and liposomal delivery systems as promising strategies for MSC rejuvenation and regenerative medicine.