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

Kuchler‐Bopp, Sabine; Bagnard, Dominique; Van‐Der‐Heyden, Michael; Idoux‐Gillet, Ysia; Strub, Marion; Gegout, Hervé; Lesot, Hervé; Benkirane‐Jessel, Nadia; Keller, Laetitia

doi:10.1002/term.2648

Cited by 10 publications

(8 citation statements)

References 54 publications

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“…Our results for osteoblasts of the alveolar bone correspond to the current state of research, which increasingly accepts an important function of Sema3A-dependent signaling for dental hard tissue formation and bone remodeling in the periodontium and in vitro [ 43 , 44 ]. From previous studies, it remained unclear what effects mechanical forces might have on Sema3A signaling.…”

Section: Discussionsupporting

confidence: 86%

A Potential Role of Semaphorin 3A during Orthodontic Tooth Movement

Şen

Lux

Erber

2021

IJMS

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Background: Induced tooth movement during orthodontic therapy requires mechano-induced bone remodeling. Besides various cytokines and growth-factors, neuronal guidance molecules gained attention for their roles in bone homeostasis and thus, potential roles during tooth movement. Several neuronal guidance molecules have been implicated in the regulation of bone remodeling. Amongst them, Semaphorin 3A is particular interesting as it concurrently induces osteoblast differentiation and disturbs osteoclast differentiation. Methods: Mechano-regulation of Sema3A and its receptors PlexinA1 and Neuropilin (RT-qPCR, WB) was evaluated by applying compressive and tension forces to primary human periodontal fibroblasts (hPDLF) and alveolar bone osteoblasts (hOB). The association of the transcription factor Osterix (SP7) and SEMA3A was studied by RT-qPCR. Mechanisms involved in SEMA3A-mediated osteoblast differentiation were assessed by Rac1GTPase pull-downs, β-catenin expression analyses (RT-qPCR) and nuclear translocation assays (IF). Osteogenic markers were analyzed by RT-qPCR. Results: SEMA3A, PLXNA1 and NRP1 were differentially regulated by tension or compressive forces in hPDLF. Osterix (SP7) displayed the same pattern of regulation. Recombinant Sema3A induced the activation of Rac1GTPase, the nuclear translocation of β-catenin and the expression of osteogenic marker genes. Conclusion: Sema3A, its receptors and Osterix are regulated by mechanical forces in hPDLF. SEMA3A upregulation was associated with Osterix (SP7) modulation. Sema3A-enhanced osteogenic marker gene expression in hOB might be dependent on a pathway involving Rac1GTPase and β-catenin. Thus, Semaphorin 3A might contribute to bone remodeling during induced tooth movement.

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Section: Discussionsupporting

confidence: 86%

A Potential Role of Semaphorin 3A during Orthodontic Tooth Movement

Şen

Lux

Erber

2021

IJMS

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“…The semaphorin proteins are well known axonal guidance cues reported to be active in a variety of tissues ( Kitsukawa et al, 1997 ; Pasterkamp et al, 2003 ; Ding et al, 2007 ; Kang et al, 2007 ; Kolk et al, 2009 ; Kopp et al, 2010 ; Coutiño and Mayor, 2021 ; Limoni, 2021 ) including dental pulp tissues ( Lillesaar and Fried, 2004 ; Maurin et al, 2005 ; Moe et al, 2012 ; Sijaona et al, 2012 ; Shrestha et al, 2014 ; Kuchler-Bopp et al, 2018 ). One research group investigated the expression profiles of all the semaphorins in M1s from E13 through P9.…”

Section: Discussionmentioning

confidence: 99%

Tgfbr2 in Dental Pulp Cells Guides Neurite Outgrowth in Developing Teeth

Stanwick

Barkley

Serra

et al. 2022

Front. Cell Dev. Biol.

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Transforming growth factor β (TGFβ) plays an important role in tooth morphogenesis and mineralization. During postnatal development, the dental pulp (DP) mesenchyme secretes neurotrophic factors that guide trigeminal nerve fibers into and throughout the DP. This process is tightly linked with dentin formation and mineralization. Our laboratory established a mouse model in which Tgfbr2 was conditionally deleted in DP mesenchyme using an Osterix promoter-driven Cre recombinase (Tgfbr2cko). These mice survived postnatally with significant defects in bones and teeth, including reduced mineralization and short roots. Hematoxylin and eosin staining revealed reduced axon-like structures in the mutant mice. Reporter imaging demonstrated that Osterix-Cre activity within the tooth was active in the DP and derivatives, but not in neuronal afferents. Immunofluorescence staining for β3 tubulin (neuronal marker) was performed on serial cryosections from control and mutant molars on postnatal days 7 and 24 (P7, P24). Confocal imaging and pixel quantification demonstrated reduced innervation in Tgfbr2cko first molars at both stages compared to controls, indicating that signals necessary to promote neurite outgrowth were disrupted by Tgfbr2 deletion. We performed mRNA-Sequence (RNA-Seq) and gene onotology analyses using RNA from the DP of P7 control and mutant mice to investigate the pathways involved in Tgfbr2-mediated tooth development. These analyses identified downregulation of several mineralization-related and neuronal genes in the Tgfbr2cko DP compared to controls. Select gene expression patterns were confirmed by quantitative real-time PCR and immunofluorescence imaging. Lastly, trigeminal neurons were co-cultured atop Transwell filters overlying primary Tgfbr2f/f DP cells. Tgfbr2 in the DP was deleted via Adenovirus-expressed Cre recombinase. Confocal imaging of axons through the filter pores showed increased axonal sprouting from neurons cultured with Tgfbr2-positive DP cells compared to neurons cultured alone. Axon sprouting was reduced when Tgfbr2 was knocked down in the DP cells. Immunofluorescence of dentin sialophosphoprotein in co-cultured DP cells confirmed reduced mineralization potential in cells with Tgfbr2 deletion. Both our proteomics and RNA-Seq analyses indicate that axonal guidance cues, particularly semaphorin signaling, were disrupted by Tgfbr2 deletion. Thus, Tgfbr2 in the DP mesenchyme appears to regulate differentiation and the cells’ ability to guide neurite outgrowth during tooth mineralization and innervation.

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“…Sema3A-dependent Nrp1 activation was also shown to trigger odontoblast differentiation of dental pulp stem cells via Wnt/β-catenin signaling [ 111 ]. Increasingly, links to tooth development and thus to hard tissue formation are also being described for neuronal functions of Sema3A [ 11 ], opening perspectives for the regeneration of dental hard tissue in vitro (“bioengineered teeth”) [ 112 ].…”

Section: Bone Remodelingmentioning

confidence: 99%

Neuronal Guidance Molecules in Bone Remodeling and Orthodontic Tooth Movement

Şen

Erber

2022

IJMS

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During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted.

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

Cited by 10 publications

References 54 publications

A Potential Role of Semaphorin 3A during Orthodontic Tooth Movement

A Potential Role of Semaphorin 3A during Orthodontic Tooth Movement

Tgfbr2 in Dental Pulp Cells Guides Neurite Outgrowth in Developing Teeth

Neuronal Guidance Molecules in Bone Remodeling and Orthodontic Tooth Movement

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