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.
Highlights
Aging is an inherent physiological process of life, characterized by impairment of biological processes in living organisms with loss of function and multiple diseases, and has been recently introduced as a new disease in the International Classification of Diseases released by the World Health Organization [1]
The first is related to indirect inhibition of the ability of inflammatory cells (i.e., T lymphocytes, dendritic cells, natural killer (NK) cells, and B lymphocytes) to proliferate and secrete inflammatory cytokines, through the release of anti-inflammatory cytokines, including transforming growth factor-beta (TGF-β), hepatocytes growth factor (HGF), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), or human leukocyte antigen-G5 (HLA-G5) by the Mesenchymal stem cells (MSCs) [10,11,12,13,14]
Periodontitis is defined as an inflammatory disease of the tooth-supporting tissues caused by specific microorganisms, resulting in progressive destruction of the periodontal ligament and alveolar bone with the periodontal pocket formation and/or gingival recession [30]
Summary
Aging is an inherent physiological process of life, characterized by impairment of biological processes in living organisms with loss of function and multiple diseases, and has been recently introduced as a new disease in the International Classification of Diseases released by the World Health Organization [1]. Mesenchymal stem cells (MSCs) are one of the multipotent stromal cell sources for tissue regeneration. They can be isolated from the bone marrow, and from several adult tissues, including adipose tissue, and those in the orofacial region, such as dental pulp, gingiva, and periodontal ligament [6,7,8]. The first is related to indirect inhibition of the ability of inflammatory cells (i.e., T lymphocytes, dendritic cells, natural killer (NK) cells, and B lymphocytes) to proliferate and secrete inflammatory cytokines, through the release of anti-inflammatory cytokines, including transforming growth factor-beta (TGF-β), hepatocytes growth factor (HGF), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), or human leukocyte antigen-G5 (HLA-G5) by the MSCs [10,11,12,13,14]. The other inhibition mechanism is based on a direct cell-to-cell contact that induces immune cell apoptosis through the FAS/FASL, leading to the regulatory T cell differentiation and immune tolerance [15]
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