Abstract
Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblast for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts. We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: “young” from 18 to 22 years old, “middle-aged” from 30 to 48 years old and “aged” over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblast compared to young serum. Myofibroblastic differentiation, measured through alpha-smooth muscle actin (α-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of α-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro-inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors. In old rat wound there is an increased of staining for TNF compared to young wound. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A.X phosphorylated at Ser139. Moreover, we detected an increased frequency of γ-H2A.X-positive cells in aged rat gingival tissues. The present study suggests that serum factors present in middle-aged and aged individuals may be responsible, at least in part, for the altered responses observed during wound healing in aging.
Highlights
The proportion of people over 60 years old is growing faster than any other age group
Coagulation is activated through the formation of a fibrin clot that serves as a temporary matrix, providing a mesh of fibrin and a reservoir of cytokines and growth factors like Platelet Derived Growth Factor (PDGF), TGFβ1 and 2, EGF, Vascular Endothelial Growth Factor (VEGF), human gingival fibroblasts (HGF), FGF-2, RANTES, MIP-1α and IL8 [3, 4]
Our study suggests that aging may have an early manifestation in serum related to the variations in some inflammatory cytokines and growth factors
Summary
The proportion of people over 60 years old is growing faster than any other age group. Coagulation is activated through the formation of a fibrin clot that serves as a temporary matrix, providing a mesh of fibrin and a reservoir of cytokines and growth factors like PDGF, TGFβ1 and 2, EGF, VEGF, HGF, FGF-2, RANTES, MIP-1α and IL8 [3, 4]. Using the parabiosis animal model, that connects the circulatory system of young and old animals, previous studies have described an improvement in the repair of aged bone fracture [7] and muscle lesions in aged conditions [8] and reversion of age related impairments in cognitive functions and synaptic plasticity in mice [9] These studies have suggested that growth factors present in the blood of aged subjects may play a detrimental role in wound healing. The role of blood-derived factors in oral wound healing remains unknown
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