Denervation during mandibular distraction osteogenesis results in impaired bone formation

Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandi...

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Published in:Scientific reports 2023-02, Vol.13 (1), p.2097-2097, Article 2097
Main Authors: Tevlin, Ruth, Griffin, Michelle, Chen, Kellen, Januszyk, Michael, Guardino, Nick, Spielman, Amanda, Walters, Shannon, Gold, Garry Evan, Chan, Charles K. F., Gurtner, Geoffrey C., Wan, Derrick C., Longaker, Michael T.
Format: Article
Language:English
Subjects:
631/136/815/816
631/532/489
692/698/1671/63
Animals
Bone growth
Bone Regeneration
Denervation
Distraction osteogenesis
Fibromodulin
Humanities and Social Sciences
Humans
Mandible
Mandible - physiology
Mice
Mice, Inbred C57BL
multidisciplinary
Neural crest
Osteogenesis
Osteogenesis - genetics
Osteogenesis, Distraction
Osteotomy
Peripheral nerves
Regeneration
Science
Science (multidisciplinary)
Sequence analysis
Stem cell transplantation
Stem cells
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Summary:Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy (“DO Den”) and DO with IAN intact (“DO Inn”). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-27921-9