Aging-Affected MSC Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model

Abstract

Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of MSC function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα)+ MSCs, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of MSC function showed that the expression of surface antigen markers for MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged MSCs were significantly declined compared to those of young MSCs. Moreover, a significantly higher proportion of aged MSCs were positive for the senescence-associated β galactosidase activity. Importantly, aged MSCs presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged MSCs to induce T cell apoptosis in co-cultures compared with young MSCs. In summary, this is the first study showing that aging-induced impairment of MSC function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration.

Epithelial Cell Rests of Malassez Provide a Favorable Microenvironment for Ameliorating the Impaired Osteogenic Potential of Human Periodontal Ligament Stem Cells

“…Our team also detected that the application of the Wnt signaling antagonist DKK1 led to an increase in osteogenic differentiation in PDLSCs derived from the inflammatory microenvironment (Sun et al, 2017). Earlier studies have found that aging is also a chronic inflammatory process (Zhang et al, 2012;Aung et al, 2020), which implicates similar trends of cells from donors with periodontitis and aged donors. In this study, the results showed that P-GSK-3β and active-β-catenin decreased in the co-culture system, while GSK-3β and total-β-catenin remained unmodified, suggesting the suppression of the Wnt pathway in PDLSCs from an impaired microenvironment after co-cultured with ERM (Figure 6).…”

“…For instance, the efficacy of periodontal regeneration declines in diabetes compared with healthy animals (Kim et al, 2020;Nguyen et al, 2020). Furthermore, PDLSCs from aged microenvironment exhibited reduced colony-forming ability, proliferative, migratory and osteogenic potential than PDLSCs from healthy PDL (Zheng et al, 2009;Wu et al, 2015;Aung et al, 2020). For PDLSCs isolated from periodontitis, our team previously found that the proliferative capacity of them increased but the osteogenic potential of them was significantly lower than that of PDLSCs isolated from healthy PDL (Liu et al, 2011;Tang et al, 2016;Sun et al, 2017).…”

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

“…An in vitro study revealed that the expression of surface antigen markers of MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenesis of aged MSCs were significantly lower than those of young MSCs. These results suggested that aging-induced impairment of MSC function is potentially correlated with progressive periodontal tissue deterioration [72]. Recently, the ligature-induced bone loss method has been modified for dental implants to investigate peri-implantitis.…”

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo

“…After the 3-week culture period, the cells were then washed with PBS and stained with 0.1% toluidine blue contained in 1% PFA overnight. On the following day, dishes were washed to remove excess dye, and only stained clusters containing more than 50 cells were counted as colonies [ 28 ].…”