RvE1 Promotes Axin2+ Cell Regeneration and Reduces Bacterial Invasion

Abstract

Vital pulp therapy and root canal therapy (RCT) are the dominant treatment for irreversible pulpitis. While the success rate of these procedures is favorable, they have some limitations. For instance, RCT leads to removing significant dentin in the coronal third of the tooth that increases root-fracture risk, which forces tooth removal. The ideal therapeutic goal is dental pulp regeneration, which is not achievable with RCT. Specialized proresolving mediators (SPMs) are well known for inflammatory resolution. The resolution of inflammation and tissue restoration or regeneration is a dynamic and continuous process. SPMs not only have potent immune-modulating functions but also effectively promote tissue homeostasis and regeneration. Resolvins have been shown to promote dental pulp regeneration. The purpose of this study was to explore further the cellular target of Resolvin E1 (RvE1) therapy in dental pulp regeneration and the impact of RvE1 in infected pulps. We investigated the actions of RvE1 on experimentally exposed pulps with or without microbial infection in an Axin2 Cre-Dox; Ai14 genetically defined mouse model. Our results showed RvE1 promoted Axin2-tdTomato+ cell expansion and odontoblastic differentiation after direct pulp capping in the mouse, which we used to mimic reversible pulpitis cases in the clinic. In cultured mouse dental pulp stem cells (mDPSCs), RvE1 facilitated Axin2-tdTomato+ cell proliferation and odontoblastic differentiation and also rescued impaired functions after lipopolysaccharide stimulation. In infected pulps exposed to the oral environment for 24 h, RvE1 suppressed inflammatory infiltration, reduced bacterial invasion in root canals, and prevented the development of apical periodontitis, while its proregenerative impact was limited. Collectively, topical treatment with RvE1 facilitated dental pulp regenerative properties by promoting Axin2-expressing cell proliferation and differentiation. It also modulated the resolution of inflammation, reduced infection severity, and prevented apical periodontitis, presenting RvE1 as a novel therapeutic for treating endodontic diseases.

Lipid mediators in neutrophil biology: inflammation, resolution and beyond

“…prostaglandins, COX-2 expression, leukotrienes) and pro-inflammatory cytokines to promote tissue repair in a manner that does not compromise host defense [2,18,33,34]. SPMs are proven to potently limit excessive neutrophil infiltration increase neutrophil phagocytosis in various tissues and regulate neutrophil-mediated damage in abdominal aortic aneurysms [71], cystic fibrosis [72], atherosclerosis [73] asthma [74], liver injury [75], and UV-induced inflammation, coronary artery contractions [76], infections [77][78][79][80][81], cornea [77], and gingivitis [82,83] and during second organ ischemia reperfusion [59].…”

Is Lipid Metabolism of Value in Cancer Research and Treatment? Part II: Role of Specialized Pro-Resolving Mediators in Inflammation, Infections, and Cancer

“…In cultured mouse dental pulp stem cells (mDPSCs), RvE1 facilitated AXin2-tdTomato + cell proliferation, odontoblastic differentiation, and rescued impaired functions after lipopolysaccharide stimulation. In addition, RvE1 in this model reduced infection severity, prevented apical periodontitis, and accelerated the resolution of inflammation [ 101 ]. In a murine model of hypertension induced with angiotensin II, RvE1 potently lowered blood pressure, reduced aortic media thickness and infiltration of inflammatory macrophages and T cells while attenuating aortic fibrosis, and mitigated vascular smooth muscle cell transformation and proliferation [ 102 ].…”

Resolvin D2-induced reparative dentin and pulp stem cells after pulpotomy in a rat model

“…In contrast, SPMs are immunosuppressive and can combat infections [ 13 ]. Another type of resolvin (Resolvin E1: RvE1) has been reported to resolute inflammation and to reduce infection, finally induced stem cell-related dentin repairment [ [18] , [19] , [20] , [21] ]. On the other hand, RvD2 inhibits alveolar bone resorption and exerts anti-inflammatory effects in a mouse periodontitis model [ 22 ].…”