Macrophage modulation of dental pulp stem cell activity during tertiary dentinogenesis

Abstract

The interaction between immune cells and stem cells is important during tissue repair. Macrophages have been described as being crucial for limb regeneration and in certain circumstances have been shown to affect stem cell differentiation in vivo. Dentine is susceptible to damage as a result of caries, pulp infection and inflammation all of which are major problems in tooth restoration. Characterising the interplay between immune cells and stem cells is crucial to understand how to improve natural repair mechanisms. In this study, we used an in vivo damage model, associated with a macrophage and neutrophil depletion model to investigate the role of immune cells in reparative dentine formation. In addition, we investigated the effect of elevating the Wnt/β-catenin pathway to understand how this might regulate macrophages and impact upon Wnt receiving pulp stem cells during repair. Our results show that macrophages are required for dental pulp stem cell activation and appropriate reparative dentine formation. In addition, pharmacological stimulation of the Wnt/β-catenin pathway via GSK-3β inhibitor small molecules polarises macrophages to an anti-inflammatory state faster than inert calcium silicate-based materials thereby accelerating stem cell activation and repair. Wnt/β-catenin signalling thus has a dual role in promoting reparative dentine formation by activating pulp stem cells and promoting an anti-inflammatory macrophage response.

Facilitating Reparative Dentin Formation Using Apigenin Local Delivery in the Exposed Pulp Cavity

“…Specifically, 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). 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); however, 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.…”

“…Inflammatory and immunological aspects of dental pulp repair should be taken into consideration during cavity treatment (Smith, 2002;Goldberg et al, 2008). The widely accepted paradigm both in the pulp and other bodily sites is that healing can only occur after removal of the infection, enabling a significant dampening of inflammation (Duncan and Cooper, 2020;Neves et al, 2020). Therefore, 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).…”

3D Visualization of Dynamic Cellular Reaction of Pulpal CD11c+ Dendritic Cells against Pulpitis in Whole Murine Tooth

“…Nevertheless, the cellular identity of these greatly increased pulpal CD11c+ cells with an arrangement in a barrier-like formation ( Figure 3 d and Supplementary Video S3 ) remains undetermined and requires further investigation. One candidate for their identity is macrophages known to have a pivotal role in dentin repair in a pulpitis murine model by mediating dental pulp stem cell activity [ 37 ]. Macrophages, one of the mononuclear phagocytes, are immune cells essential for both the inflammatory response (M1-like) and anti-inflammatory response (M2-like) [ 38 ].…”

Inflammatory Response Mechanisms of the Dentine–Pulp Complex and the Periapical Tissues

“…Stem cells in the dental pulp are located in the perivascular niche [ 160 ] and remain quiescent until they are recruited to the site of injury upon chemotactic signaling, they migrate and differentiate into a mineralizing cell type reminiscent of odontoblasts [ 161 ]. However, pulp stem cells also express TLRs and are capable of pathogen recognition [ 22 ], but may also be recruited after activation by macrophages [ 162 ].…”