Pathophysiology and regeneration of the pulpodental complex

Project leader  : J-C. Farges

Participant  : M. Ducret, S. Gobert, M. Bekhouche, E. Aubert-Foucher, M. Pasdeloup

Our general aim is to elucidate the immune, inflammatory, healing and regenerative events triggered in the human dental pulp by the oral bacteria present in caries lesions. We are currently more specifically interested in the two following topics :

  1. The odontoblast-dependent pulp defence mechanisms

Penetration of oral cariogenic bacteria into the enamel then dentin triggers an immune and inflammatory reaction in the underlying dental pulp intended to combat the microbial invaders. Owing to both their specific localization at the pulp-dentin interface and the embedding of their long cellular processes in dentin, odontoblasts are the first pulpal cells encountered by dentin-invading pathogens and their released products. We have previously shown in vitro that microorganism sensing by specific receptors of the odontoblast cell membrane stimulates the production of antibacterial molecules such as nitric oxide (NO), acute phase proteins including the lipopolysaccharide-binding protein (LBP), and pro-inflammatory cytokines and chemokines (IL-6, IL-8, CCL2, CXCL1, CXCL2, CXCL8, CXCL10) the function of which is to activate the pulp immune cells (macrophages, dendritic cells, T cells) close to the lesion.

Our two goals: (i) to confirm in vivo the role of odontoblasts as initiators of the dental pulp immune/inflammatory response to cariogenic microorganisms, and (ii) to determine the influence of pulp immune cells on the differentiation of local mesenchymal stem/progenitor cells into odontoblasts.

  1. The regeneration of a human pulp-dentin complex by mesenchymal stem/progenitor cells seeded in innovative biomaterials (Regepulp project)

Without treatment, developing caries lesions induce an irreversible inflammation in the human dental pulp which requires the devitalization of the tooth that is the removal of the damaged pulp tissue located in the endodontic space in the centre of the tooth then the filling of the endodontic space with an inert gutta percha-based biomaterial. This therapeutic strategy is not satisfactory because it prevents the tooth to sense future noxious stimuli and to defend itself in the case of a new infection. In this context, innovative strategies allowing for the regeneration of a pulp-dentin complex ad integrum are needed. Our two objectives are : (i) to further understand the physiopathological mechanisms underlying human pulp-dentin healing and regeneration, and (ii) to design, by using tissue engineering techniques, cell-based medicinal products that associate innovative biomaterials and specific populations of mesenchymal stem/progenitor cells from dental pulp, bone marrow, adipose tissue or Wharton’s jelly.


Selected publications : 

-Bekhouche M, Bolon M, Charriaud F, Lamrayah M, Da Costa D, Primard C, Costantini A, Pasdeloup M, Gobert S, Mallein-Gerin F, Verrier B, Ducret M, Farges JC. Development of an antibacterial nanocomposite hydrogel for human dental pulp engineering. J Mater Chem B. 2020 Sep 23;8(36):8422-8432. doi: 10.1039/d0tb00989j. PMID: 32804177

Ducret M, Farges JC, Pasdeloup M, Perrier-Groult E, Mueller A, Mallein-Gerin F, Fabre H. Phenotypic Identification of Dental Pulp Mesenchymal Stem/Stromal Cells Subpopulations with Multiparametric Flow Cytometry.

Methods Mol Biol. 2019;1922:77-90. doi: 10.1007/978-1-4939-9012-2_8.

– Ducret M, Montembault A, Josse J, Pasdeloup M, Celle A, Benchrih R, Mallein-Gerin F, Alliot-Licht B, David L, Farges JC. Design and characterization of a chitosan-enriched fibrin hydrogel for human dental pulp regeneration. Dent Mater. 2019 Apr;35(4):523-533. doi: 10.1016/ Epub 2019 Jan 31.

Ducret M, Fabre H, Celle A, Mallein-Gerin F, Perrier-Groult E, Alliot-Licht B, Farges JC. Current challenges in human tooth revitalization. Biomed Mater Eng. 2017;28(s1):S159-S168. PMID: 28372291. doi: 10.3233/BME-171637.

Ducret M, Fabre H, Degoul O, Atzeni G, McGuckin C, Forraz N, Mallein-Gerin F, Perrier-Groult E, Alliot-Licht B, Farges JC. Immunophenotyping Reveals the Diversity of Human Dental Pulp Mesenchymal Stromal Cells In vivo and Their Evolution upon In vitro Amplification. Front Physiol. 2016 Nov 8;7:512. eCollection 2016. PMID: 27877132. doi: 10.3389/fphys.2016.00512

Park S-H, Ye L, Love RM, Farges J-C, Yumoto H. Inflammation of the Dental Pulp. Mediat Inflamm 2015; Article ID 980196. doi: org/10.1155/2015/980196.

– Ducret M, Fabre H, Degoul O, Atzeni G, Mcguckin C, Forraz N, Alliot-Licht B, Mallein-Gerin F, Perrier-Groult E, Farges J-C. Manufacturing of dental pulp cell-based products from human third molars : current strategies and future investigations. Front Physiol 2015 ;6:213. doi:10.3389/fphys.2015.00213.

– Ducret M, Fabre H, Farges J-C, Degoul O, Atzeni G, Mcguckin C, Forraz N, Mallein-Gerin F, Perrier-Groult E. Production of human dental pulp cells with a medicinal manufacturing approach. J Endod 2015 ; 41(9):1492-9. doi : 10.1016/j.joen.2015.05.017.

– Farges J-C, Bellanger A, Ducret M, Aubert-Foucher E, Richard B, Alliot-Licht B, Bleicher F, Carrouel F. Human odontoblast-like cells produce nitric oxide with antibacterial activity upon TLR2 activation. Front Physiol 2015 ;6:185. doi : 10.3389/fphys.2015.00185.

– Gaudin A, Renard E, Hill M, Bouchet-Delbos L, Bienvenu-Louvet G, Farges J-C, Cuturi M-C, Alliot-Licht B. Phenotypic analysis of immunocompetent cells in healthy human dental pulp. J Endod 2015 ;41(5):621-7. doi : 10.1016/j.joen.2015.01.005.

– Bonnamain V, Thinard R, Sergent-Tanguy S, Huet P, Bienvenu G, Naveilhan P, Farges J-C, Alliot-Licht B. Human dental pulp stem cells cultured in serum-free supplemented medium. Front Physiol 2013 ;4:357. doi:10.3389/fphys.2013.00357.

– Farges J-C, Alliot-Licht B, Baudouin C, Msika P, Bleicher F, Carrouel F. Odontoblast control of dental pulp inflammation triggered by cariogenic bacteria. Front Physiol 2013 ;4:326. doi : 10.3389/fphys.2013.00326.

Collaborations : 

– Pr Brigitte ALLIOT-LICHT, INSERM U1064 & Faculté d’Odontologie, Université de Nantes.

– Pr Laurent DAVID & Dr Alexandra MONTENBAULT, Laboratoire d’Ingénierie des Matériaux Polymères (IMP-UMR5223), Université Lyon 1, Villeurbanne.

– Pr Colin McGUCKIN & Dr Nico FORRAZ, CTI-BIOTECH, Meyzieu.

– Pr Paul COOPER, Oral Biology, School of Dentistry, Collège of Medical and Dental Sciences, University of Birmingham, UK.