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Regeneration of pulpo-dentinal-like complex by a group of unique multipotent CD24a positive stem cells

ABSTRACT: In this study, through three-dimensional spheroid culture, a group of unique multipotent stem cells were identified from mouse dental papilla, called multipotent dental pulp-regenerative stem cells (MDPSCs). MDPSCs exhibited enhanced osteo/odontogenic differentiation capabilities and could form regenerative dentin and neurovascular-like structures that mimicked the native teeth in vivo. Further analysis revealed that CD24a was the bona fide marker for MDPSCs and their expansion was highly dependent on the expression of a key transcriptional factor Sp7. Finally, CD24a positive cells could be detected in primary dental papilla in mice and human, suggesting MDPSCs resided in their native niches. Together, our study has identified a novel group of multipotent pulpregenerative stem cells with defined molecular markers for the potential treatment of pulpitis and pulp necrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE138372 | GEO | 2020/04/15

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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Regeneration of pulpo-dentinal-like complex by a group of unique multipotent CD24a positive stem cells

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