Micronano Titanium Accelerates Mesenchymal Stem Cells Aging through the Activation of Senescence-Associated Secretory Phenotype.

ABSTRACT

Stem cell senescence is one of the most representative events of organism aging and is responsible for many physiological abnormalities and disorders. In the scenario of orthopedic disease treatment, stem cell aging may affect the implantation outcome and even lead to operation failure. To explore whether stem cell aging will affect the osteointegration effect of titanium implant, a widely used micronano titanium (MNT) was fabricated. We first verified the expected osteointegration effect of the MNT, which could be attributed to the improvement of stem cell adhesion and osteogenic differentiation. Then, we obtained aged-derived bone marrow mesenchymal stem cells (BMSCs) and studied their biological behaviors on MNT both in vitro and in vivo. We found that compared with normal rats, MNT did not significantly improve the osteointegration in aged rats. Compared with normal rats, fewer endogenous stem cells were observed at the implant-host interface, and the expression of p21 (senescence marker) was also higher. We further confirmed that MNT promoted the nuclear localization of NF-κB in senescent stem cells through the activation of p38 MAPK, thereby inducing the occurrence of the senescence-associated secretory phenotype (SASP) and ultimately leading to the depletion of the stem-cell pool at the implant-host interface. However, the activation of p38 MAPK can still promote the osteogenic differentiation of nonsenescent BMSCs. These results showed an interesting paradoxical balance between osteogenesis and senescence on MNT surfaces and also provided insights for the design of orthopedic implants for aging patients.