Immunomodulation stimulates the innervation of engineered tooth organ

PLoS One. 2014 Jan 22;9(1):e86011. doi: 10.1371/journal.pone.0086011. eCollection 2014.


The sensory innervation of the dental mesenchyme is essential for tooth function and protection. Sensory innervation of the dental pulp is mediated by axons originating from the trigeminal ganglia and is strictly regulated in time. Teeth can develop from cultured re-associations between dissociated dental epithelial and mesenchymal cells from Embryonic Day 14 mouse molars, after implantation under the skin of adult ICR mice. In these conditions however, the innervation of the dental mesenchyme did not occur spontaneously. In order to go further with this question, complementary experimental approaches were designed. Cultured cell re-associations were implanted together with trigeminal ganglia for one or two weeks. Although axonal growth was regularly observed extending from the trigeminal ganglia to all around the forming teeth, the presence of axons in the dental mesenchyme was detected in less than 2.5% of samples after two weeks, demonstrating a specific impairment of their entering the dental mesenchyme. In clinical context, immunosuppressive therapy using cyclosporin A was found to accelerate the innervation of transplanted tissues. Indeed, when cultured cell re-associations and trigeminal ganglia were co-implanted in cyclosporin A-treated ICR mice, nerve fibers were detected in the dental pulp, even reaching odontoblasts after one week. However, cyclosporin A shows multiple effects, including direct ones on nerve growth. To test whether there may be a direct functional relationship between immunomodulation and innervation, cell re-associations and trigeminal ganglia were co-implanted in immunocompromised Nude mice. In these conditions as well, the innervation of the dental mesenchyme was observed already after one week of implantation, but axons reached the odontoblast layer after two weeks only. This study demonstrated that immunodepression per se does stimulate the innervation of the dental mesenchyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / drug effects
  • Axons / physiology
  • Cells, Cultured
  • Cyclosporine / pharmacology*
  • Dental Pulp / drug effects
  • Dental Pulp / embryology
  • Dental Pulp / innervation
  • Female
  • Immunosuppressive Agents / pharmacology*
  • Male
  • Mesoderm / drug effects
  • Mesoderm / embryology
  • Mesoderm / innervation
  • Mice
  • Mice, Inbred ICR
  • Mice, Inbred Strains
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Molar / drug effects*
  • Molar / embryology
  • Molar / innervation
  • Odontoblasts / cytology
  • Odontoblasts / drug effects
  • Odontoblasts / physiology
  • Odontogenesis
  • Time Factors
  • Tissue Engineering / methods*
  • Tissue Transplantation / methods
  • Trigeminal Ganglion / drug effects
  • Trigeminal Ganglion / physiology
  • Trigeminal Ganglion / ultrastructure


  • Immunosuppressive Agents
  • Cyclosporine

Grant support

Tunay Kökten was funded by the Dental School from the Université de Strasbourg. This work was partially supported by the project NanoOscar from the ANR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.