J Tissue Eng Regen Med. 2018 Apr;12(4):e2151-e2161. doi: 10.1002/term.2648. Epub 2018 Mar 25.

Semaphorin 3A receptor inhibitor as a novel therapeutic to promote innervation of bioengineered teeth.

Kuchler-Bopp S¹, Bagnard D², Van-Der-Heyden M², Idoux-Gillet Y^1,3, Strub M^1,3,4, Gegout H^1,3, Lesot H¹, Benkirane-Jessel N^1,3, Keller L^1,3.

Abstract

The sensory innervation of the dental pulp is essential for tooth function and protection. It is mediated by axons originating from the trigeminal ganglia and is spatio-temporally regulated. We have previously shown that the innervation of bioengineered teeth can be achieved only under immunosuppressive conditions. The aim of this study was to develop a model to determine the role of Semaphorin 3A (Sema3A) in the innervation of bioengineered teeth. We first analysed innervation of the dental pulp of mandibular first molars in newborn (postnatal day 0: PN0) mice deficient for Sema3A (Sema3A^-/- ), a strong inhibitor of axon growth. While at PN0, axons detected by immunostaining for peripherin and NF200 were restricted to the peridental mesenchyme in Sema3A^+/+ mice, they entered the dental pulp in Sema3A^-/- mice. Then, we have implanted cultured teeth obtained from embryonic day-14 (E14) molar germs of Sema3A^-/- mice together with trigeminal ganglia. The dental pulps of E14 cultured and implanted Sema3A^-/- teeth were innervated, whereas the axons did not enter the pulp of E14 Sema3A^+/+ cultured and implanted teeth. A "Membrane Targeting Peptide NRP1," suppressing the inhibitory effect of Sema3A, has been previously identified. The injection of this peptide at the site of implantation allowed the innervation of the dental pulp of bioengineered teeth obtained from E14 dental dissociated mesenchymal and epithelial cells reassociations of ICR mice. In conclusion, these data show that inhibition of only one axon repellent molecule, Sema3A, allows for pulp innervation of bioengineered teeth.