Abstract
Apigenin, a natural product belonging to the flavone class, affects various cell physiologies, such as cell signaling, inflammation, proliferation, migration, and protease production. In this study, apigenin was applied to mouse molar pulp after mechanically pulpal exposure to examine the detailed function of apigenin in regulating pulpal inflammation and tertiary dentin formation. In vitro cell cultivation using human dental pulp stem cells (hDPSCs) and in vivo mice model experiments were employed to examine the effect of apigenin in the pulp and dentin regeneration. In vitro cultivation of hDPSCs with apigenin treatment upregulated bone morphogenetic protein (BMP)- and osteogenesis-related signaling molecules such as BMP2, BMP4, BMP7, bone sialoprotein (BSP), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN) after 14 days. After apigenin local delivery in the mice pulpal cavity, histology and cellular physiology, such as the modulation of inflammation and differentiation, were examined using histology and immunostainings. Apigenin-treated specimens showed period-altered immunolocalization patterns of tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), NESTIN, and transforming growth factor (TGF)-β1 at 3 and 5 days. Moreover, the apigenin-treated group showed a facilitated dentin-bridge formation with few irregular tubules after 42 days from pulpal cavity preparation. Micro-CT images confirmed obvious dentin-bridge structures in the apigenin-treated specimens compared with the control. Apigenin facilitated the reparative dentin formation through the modulation of inflammation and the activation of signaling regulations. Therefore, apigenin would be a potential therapeutic agent for regenerating dentin in exposed pulp caused by dental caries and traumatic injury.
Highlights
Reparative dentinogenesis is the biological regeneration of dentin from new odontoblast-like cells when a dental injury is severe and reaches up to the dental pulp (Smith et al, 1995; Simon et al, 2012)
Previous reports emphasized the importance of Wnt and TGFβ signaling in the development of dental pulp and odontoblasts and the reparative dentin formation (Lim et al, 2014; Hunter et al, 2015; Jung et al, 2017; Niwa et al, 2018; Ali et al, 2019)
Our results showed that both the Bmp- and the osteogenesis-related signaling molecules (i.e., BMP2, BMP4, BMP7, bone sialoprotein (BSP), RUNX2, and OCN) were significantly upregulated in the apigenin-treated specimens compared to controls after 14 days (Figure 1D and Supplementary Table 2)
Summary
Reparative dentinogenesis is the biological regeneration of dentin from new odontoblast-like cells when a dental injury is severe and reaches up to the dental pulp (Smith et al, 1995; Simon et al, 2012). Copious reports on detailed signaling molecules in dentin regeneration were prepared (Huang, 2011; Chmilewsky et al, 2014; Hunter et al, 2015; Karakida et al, 2019; Neves et al, 2020); it is still difficult to regenerate the dentin in the clinical field. These problems would result from the less focused study on controlling the inflammation in the early stage of tissue injury. Drugs that have both anti-inflammatory properties showing low cytokine stimulation levels and facilitating tissue regeneration can be considered as the supplementary agent to facilitate the reparative dentine formation (Julier et al, 2017)
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