Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP

Abstract

Periodontal ligament stem cell (PDLSC)-based tissue engineering is an important method to promote periodontal tissue regeneration. However, PDLSCs are susceptible to the effects of replicative senescence, leading to reduced proliferation and differentiation abilities and weakened tissue regeneration potential. Senolytics (the combination of dasatinib and quercetin) are drugs that inhibit cellular aging through inducing the apoptosis of senescent cells, but whether they have positive effects during the senescence of PDLSCs is unknown. The present study established a long-term in vitro culture model of PDLSCs and then analyzed the effects of senolytics on the senescence, apoptosis, and osteogenic differentiation of PDLSCs in vitro and PDLSC-based tissue regeneration in vivo. The results showed that senolytics delayed the process of aging in prolonged-cultured PDLSCs and promoted the elimination and apoptosis of senescent cells. Moreover, senolytics improved the osteogenic differentiation ability of both young and senescent PDLSCs in vitro and promoted PDLSC-based alveolar bone regeneration in vivo. Furthermore, senolytics inhibited the expression of YAP in senescent PDLSCs. Their antiaging effects were enhanced when combined with the YAP inhibitor verteporfin, but were inhibited when combined with the YAP activator NIBR-LTSi. Taken together, these findings suggest that senolytics promoted the elimination of senescent PDLSCs and enhanced senescent PDLSC-based bone regeneration, partially through the inhibition of YAP expression.