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Osteoblasts are inherently programmed to repel sensory innervation.

ABSTRACT: Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of axons. Sensory innervation is part of the neuronal network of the bone tissue with a defined spatiotemporal occurrence during bone development. Yet, the current understanding of the mechanisms regulating the map of sensory innervation in the bone tissue is still limited. Here, we demonstrated that differentiation of human mesenchymal stem cells to osteoblasts leads to a marked impairment of their ability to promote axonal growth, evidenced under sensory neurons and osteoblastic-lineage cells crosstalk. The mechanisms by which osteoblast lineage cells provide this nonpermissive environment for axons include paracrine-induced repulsion and loss of neurotrophic factors expression. We identified a drastic reduction of NGF and BDNF production and stimulation of Sema3A, Wnt4, and Shh expression culminating at late stage of OB differentiation. We noted a correlation between Shh expression profile, OB differentiation stages, and OB-mediated axonal repulsion. Blockade of Shh activity and signaling reversed the repulsive action of osteoblasts on sensory axons. Finally, to strengthen our model, we localized the expression of Shh by osteoblasts in bone tissue. Overall, our findings provide evidence that the signaling profile associated with osteoblast phenotype differentiating program can regulate the patterning of sensory innervation, and highlight osteoblast-derived Shh as an essential player in this cue-induced regulation.

SUBMITTER: Leitao L

PROVIDER: S-EPMC7220946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although neurophysiological and psychophysical proof of osseoperception is accumulating, histomorphometric evidence for the neural mechanisms of functional compensation following immediate and delayed implant loading is still lacking. For this randomized split-mouth study, six mongrel dogs randomly received one of four treatment protocols at 36 implant-recipient sites over 16 weeks (third maxillary incisor, third and fourth mandibular premolar): immediate implant placement and immediate loading (IIP+IL); delayed implant placement and delayed loading (DIP+DL); delayed implant placement and immediate loading (DIP+IL); and natural extraction socket healing (control). Histomorphometry was performed in the peri-implant bone and soft tissues within 300 µm around the implants. Immunocytochemistry and transmission electron microscopy were used to confirm the presence of neural structures and to reveal their ultrastructural characteristics, respectively. Myelinated nerve fibres densely populated the peri-implant crestal gingival and apical regions, although they were also identified in the woven bone and in the osteons near the implant threads. Compared with the control group in the mandible, the group that received IIP+IL showed a higher innervation (in N⋅mm⁻², 5.94 ± 1.12 vs. 3.15 ± 0.63, P<0.001) and smaller fibre diameter (in µm, 1.37 ± 0.05 vs. 1.64 ± 0.13, P=0.016), smaller axon diameter (in µm, 0.89 ± 0.05 vs. 1.24 ± 0.10, P=0.009) and g-ratio (0.64 ± 0.04 vs. 0.76 ± 0.05, P<0.001) in the middle region around the implants. Compared with DIP+IL in the mandible, IIP+IL had a higher nerve density (in N⋅mm⁻², 13.23 ± 2.54 vs. 9.64 ± 1.86, P=0.027), greater fibre diameter (in µm, 1.32 ± 0.02 vs. 1.20 ± 0.04, P=0.021), greater axon diameter (in µm, 0.92 ± 0.01 vs. 0.89 ± 0.03, P=0.035) and lower g-ratio (0.69 ± 0.01 vs. 0.74 ± 0.01, P=0.033) in the apical region around the implants. It may be assumed that the treatment protocol with IIP+IL is the preferred method to allow optimized peri-implant re-innervation, but further functional measurements are still required.

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Osteoblasts are inherently programmed to repel sensory innervation.

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