Abstract
Given the importance of sensory innervation in tooth vitality, the identification of signals that control nerve regeneration and the cellular events they induce is essential. Previous studies demonstrated that the complement system, a major component of innate immunity and inflammation, is activated at the injured site of human carious teeth and plays an important role in dental-pulp regeneration via interaction of the active Complement C5a fragment with pulp progenitor cells. In this study, we further determined the role of the active fragment complement C5a receptor (C5aR) in dental nerve regeneration in regards to local secretion of nerve growth factor (NGF) upon carious injury. Using ELISA and AXIS co-culture systems, we demonstrate that C5aR is critically implicated in the modulation of NGF secretion by LTA-stimulated pulp fibroblasts. The NGF secretion by LTA-stimulated pulp fibroblasts, which is negatively regulated by C5aR activation, has a role in the control of the neurite outgrowth length in our axon regeneration analysis. Our data provide a scientific step forward that can guide development of future therapeutic tools for innovative and incipient interventions targeting the dentin-pulp regeneration process by linking the neurite outgrowth to human pulp fibroblast through complement system activation.
Highlights
Dental caries is one of the most common human pathologies, affecting 90% of the U.S adult population[1]
C5a receptor (C5aR) expression is increased in lipoteichoic acid (LTA)-stimulated human pulp fibroblasts and under carious injury
As the C5a/C5aR interaction in LTA-stimulated pulp fibroblasts appears to be implicated in the modulation of nerve growth factor (NGF) secretion, we investigated the direct effect of this interaction with the NGF modulation in neurite outgrowth process
Summary
Dental caries is one of the most common human pathologies, affecting 90% of the U.S adult population[1]. Deeper injuries require more elaborated biological processes, which imply the regeneration of a full part of dentin-pulp complex including the vascularization, innervation and the production of a reparative dentin by a new generation of odontoblast-like cells[4] In both cases, nerve fiber sprouting is observed in the surviving pulp beneath the injured site[5], suggesting that the sprouting process is required for efficient dentin-pulp regeneration. Chmilewsky et al demonstrated for the first time that the complement system is activated at the injured site of human carious teeth and may play an important role in dental-pulp regeneration[15,16,17,18]. Pulp fibroblasts have previously been identified as source of regeneration signals in case of traumatic injury[21] Their capacity to secrete and guide nerve growth signals in response to caries has not been studied extensively. Our data show that C5aR is critically implicated in the NGF secretion modulation by LTA-stimulated pulp fibroblasts and this modulation regulates neurite outgrowth length in our co-culture nerve regeneration device
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