Combined senolytics induce varied phenotypic and functional responses on senescent phenotypes of mesenchymal stromal...

Mesenchymal stem cells have emerged as a pivotal focus in regenerative medicine and therapeutic innovation due to their multipotent differentiation capacity and immunomodulatory properties. A major obstacle in maintaining human MSC potency and subsequently, the use of MSCs for cellular therapy is replicative senescence, or progressive aging. This obstacle may be alleviated or overcome through the use of senolytics; a class of drugs able to clear senescent cells while leaving non-senescent cells unharmed. Our study investigates the in vitro and in vivo functional effects of the combination of two senolytics, dasatinib and quercetin, on senescent human mesenchymal stem cell populations. This was done through evaluation of dose optimization, growth rate, differentiation, gene expression, protein analyses, extracellular vesicle secretion, and bone formation in mice. Senolytic-treated populations showed inconsistent results in osteogenic and adipogenic differentiation, gene expression and protein expression. Extracellular vesicle secretion was markedly increased with senolytic treatment and new bone formation shows promising results as well. These findings present a more complete picture of the effect of combined senolytics on hMSC potency of senescent populations.