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PIEZO1 promotes odontoblast-mediated reactionary dentinogenesis via Ca2+-SEMA3A axis

ABSTRACT: The odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis by odontoblasts and the underlying mechanisms still remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in human and mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. Additionally, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type (WT) mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in reactionary dentinogenesis, mice with a conditional knockout of PIEZO1 in odontoblasts were generated, and no significant differences of teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation, and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair mediated by odontoblasts. In summary, these findings suggest that PIEZO1 enhances mineralization capacity of hOBLCs in vitro via the Ca2+/Akt/SEMA3A signaling pathway and contributes to dental pulp repair through enhancing reactionary dentinogenesis in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263258 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Enforced enhancement of H3K4me3 and H3K27ac, active chromatin marks, by inhibiting histone demethylases and deacetylases is positively linked with hard tissue formation by inducing matrix synthesis and osteo/odontogenic differentiation. However, the key endogenous epigenetic modifier of odontoblasts to regulate the expression of the genes coding dentin extracellular matrix (ECM) proteins has not been identified yet. We herein focused on IκBζ, which was originally identified as transcriptional regulator for NF-B and recently regarded as the local epigenetic modifier by independently on NF-B, and demonstrated that the IκBζ null mice exhibited thicker dentin width and narrower pulp chamber with aged mice having more drastic phenotypes. At 6 months old, dentin fluorescent labeling exhibited that dentin synthesis was significantly accelerated in the incisors of IκBζ null mice. In molars of IκBζ null mice, aggressive reactionary dentin adjacent to pulp horn was exhibited. Mechanistically, COL1A2 and COL1A1 collagen genes were increased in the odontoblasts rich fraction of IκBζ null mice than that of wild type in vivo and human odontoblasts-like cells transfected with siRNA for IκBζ than the control siRNA transfected cells in vitro. Further, the direct binding of IκBζ to COL1A2 promoter suppressed COL1A2 expression and the local active chromatin status marked with H3K4me3. By whole-genomic identification of H3K4me3 enrichments revealed that ECM and ECM organization-related gene loci were selectively activated by the knockdown of IκBζ, which consistently resulted in the up-regulation of these genes. Collectively, these results indicated that IκBζ is the key negative regulator of dentin formation in odontoblasts since the deletion of IκBζ expression enhanced dentin formation by inducing dentin ECM and ECM organization-related gene expression via altering the local chromatin status marked by H3K4me3. Therefore, IκBζ is a potential target for improving the clinical outcomes of dentin regeneration therapies such as pulp capping and pulp revitalization procedures.

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PIEZO1 promotes odontoblast-mediated reactionary dentinogenesis via Ca2+-SEMA3A axis

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