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Hypoxia-inducible factor 1α induces osteo/odontoblast differentiation of human dental pulp stem cells via Wnt/β-catenin transcriptional cofactor BCL9.

ABSTRACT: Accelerated dental pulp mineralization is a common complication in avulsed/luxated teeth, although the mechanisms underlying this remain unclear. We hypothesized that hypoxia due to vascular severance may induce osteo/odontoblast differentiation of dental pulp stem cells (DPSCs). This study examined the role of B-cell CLL/lymphoma 9 (BCL9), which is downstream of hypoxia-inducible factor 1α (HIF1α) and a Wnt/β-catenin transcriptional cofactor, in the osteo/odontoblastic differentiation of human DPSCs (hDPSCs) under hypoxic conditions. hDPSCs were isolated from extracted healthy wisdom teeth. Hypoxic conditions and HIF1α overexpression induced significant upregulation of mRNAs for osteo/odontoblast markers (RUNX2, ALP, OC), BCL9, and Wnt/β-catenin signaling target genes (AXIN2, TCF1) in hDPSCs. Overexpression and suppression of BCL9 in hDPSCs up- and downregulated, respectively, the mRNAs for AXIN2, TCF1, and the osteo/odontoblast markers. Hypoxic-cultured mouse pulp tissue explants showed the promotion of HIF1α, BCL9, and β-catenin expression and BCL9-β-catenin co-localization. In addition, BCL9 formed a complex with β-catenin in hDPSCs in vitro. This study demonstrated that hypoxia/HIF1α-induced osteo/odontoblast differentiation of hDPSCs was partially dependent on Wnt/β-catenin signaling, where BCL9 acted as a key mediator between HIF1α and Wnt/β-catenin signaling. These findings may reveal part of the mechanisms of dental pulp mineralization after traumatic dental injury.

SUBMITTER: Orikasa S

PROVIDER: S-EPMC8758693 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Wnt/beta-catenin inhibits dental pulp stem cell differentiation.

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| S-EPMC2906770 | biostudies-literature

Non-canonical Wnt signaling participates in Jagged1-induced osteo/odontogenic differentiation in human dental pulp stem cells.

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| S-EPMC9085777 | biostudies-literature

Electrical Stimulation Decreases Dental Pulp Stem Cell Osteo-/Odontogenic Differentiation.

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| S-EPMC7337168 | biostudies-literature

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| S-EPMC4892678 | biostudies-literature

Bobby Sox homology regulates odontoblast differentiation of human dental pulp stem cells/progenitors.

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| S-EPMC4062286 | biostudies-literature

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| S-EPMC3631420 | biostudies-literature

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| S-EPMC3897473 | biostudies-literature

Wnt-GSK3?/?-Catenin Regulates the Differentiation of Dental Pulp Stem Cells into Bladder Smooth Muscle Cells.

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| S-EPMC6369468 | biostudies-literature

Retinoic Acid Signal Negatively Regulates Osteo/Odontogenic Differentiation of Dental Pulp Stem Cells.

Project description:Retinoic acid (RA) signal is involved in tooth development and osteogenic differentiation of mesenchymal stem cells (MSCs). Dental pulp stem cells (DPSCs) are one of the useful MSCs in tissue regeneration. However, the function of RA in osteo/odontogenic differentiation of DPSCs remains unclear. Here, we investigated the expression pattern of RA in miniature pig tooth germ and intervened in the RA signal during osteo/odontogenic differentiation of human DPSCs. Deciduous canine (DC) germs of miniature pigs were observed morphologically, and the expression patterns of RA were studied by in situ hybridization (ISH). Human DPSCs were isolated and cultured in osteogenic induction medium with or without RA or BMS 493, an inverse agonist of the pan-retinoic acid receptors (pan-RARs). Alkaline phosphatase (ALP) activity assays, alizarin red staining, quantitative calcium analysis, CCK8 assay, osteogenesis-related gene expression, and in vivo transplantation were conducted to determine the osteo/odontogenic differentiation potential and proliferation potential of DPSCs. We found that the expression of RAR? and CRABP2 decreased during crown calcification of DCs of miniature pigs. Activation of RA signal in vitro inhibited ALP activities and mineralization of human DPSCs and decreased the mRNA expression of ALP, osteocalcin, osteopontin, and a transcription factor, osterix. With BMS 493 treatment, the results were opposite. Interference in RA signal decreased the proliferation of DPSCs. In vivo transplantation experiments suggested that osteo/odontogenic differentiation potential of DPSCs was enhanced by inversing RA signal. Our results demonstrated that downregulation of RA signal promoted osteo/odontogenic differentiation of DPSCs and indicated a potential target pathway to improve tissue regeneration.

| S-EPMC7336240 | biostudies-literature

Identification of dentinogenic cell-specific surface antigens in odontoblast-like cells derived from adult dental pulp.

Project description:BackgroundOdontoblast is a unique progenitor that plays a role in dentin formation. So far, the dentinogenic differentiation of dental pulp stem cells and the role of surface molecules of odontoblasts in dentinogenesis are not well known yet. In this study, we obtained odontoblast-like cells from human dental pulp cells and screened odontoblast-specific cell surface antigens by decoy immunization.MethodsThrough decoy immunization with intact odontoblast-like cells derived from human dental pulp cells, we constructed 12 monoclonal antibodies (mAbs) of IgG type, and their binding affinities for cell surface of odontoblast-like cells were analyzed by flow cytometry. Immunoprecipitation, mass spectrometry, and immunohistochemistry were performed to demonstrate odontoblast-specific antigens. Odontoblasts were sorted by these mAbs using magnetic-activated cell sorting system, and their mineralization efficiency was increased after sorting.ResultsWe constructed 12 mAbs of IgG type, which had a strong binding affinity for cell surface antigens of odontoblast-like cells. In human adult tooth, these mAbs accumulated in the odontoblastic layer between dentin and pulp and in the perivascular region adjacent to the blood vessels in the pulp core. Cell surface expression of the antigenic molecules was increased during odontogenic cytodifferentiation and decreased gradually as dentinogenic maturation progressed. Proteomic analysis showed that two representative antigenic molecules, OD40 and OD46, had the potential to be components for cell adhesion and extracellular matrix structures.ConclusionThese results suggest that mAbs will be useful for detecting and separating odontoblasts from the primary pulp cells and other lineage cells and will provide information on the structures of extracellular matrix and microenvironment that appears during the dentinogenic differentiation.

| S-EPMC6487011 | biostudies-literature

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