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Expression of bone morphogenetic protein-6 in dental follicle stem cells and its effect on osteogenic differentiation.

ABSTRACT: The dental follicle (DF) plays an essential role in tooth eruption via regulation of bone resorption and bone formation. Bone morphogenetic protein-6 (BMP6) expression in the DF is coincident with bone growth in the tooth crypt. DF stem cells (DFSCs) have been shown to possess strong osteogenic capability. This study aims to determine the expression of BMP6 in DFSCs and to elucidate the role of BMP6 in the osteogenesis of DFSCs. DFSCs and their non-stem cell counterpart, DF cells (DFCs), were obtained from the DFs of rat pups. We showed that expression of BMP6 was significantly higher in the DFSCs than in the DFCs. DFSCs lost osteogenic capability during in vitro expansion, and DFSCs in late passages had reduced BMP6 expression as compared to early passages of DFSCs when they were subjected to osteogenic induction. Addition of exogenous human recombinant BMP6 (hrBMP6) to the osteogenic medium dramatically enhanced the osteogenesis of the late-passage DFSCs. Knockdown of BMP6 by short interfering RNA in the DFSCs in early passages resulted in a decrease in osteogenesis, which could be restored by addition of hrBMP6. We concluded that DFSCs need to express high levels of BMP6 to maintain their osteogenesis capability. Increased BMP6 expression seen in vivo in the DF may reflect the activation of DFSCs for osteogenic differentiation for bone growth during tooth eruption.

SUBMITTER: Yao S

PROVIDER: S-EPMC4066880 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Expression of bone morphogenetic protein-6 in dental follicle stem cells and its effect on osteogenic differentiation.

Yao Shaomian S He Hongzhi H Gutierrez Dina L DL Rad Maryam Rezai MR Liu Dawen D Li Chunhong C Flanagan Michael M Wise Gary E GE

Cells, tissues, organs 20130101 6

The dental follicle (DF) plays an essential role in tooth eruption via regulation of bone resorption and bone formation. Bone morphogenetic protein-6 (BMP6) expression in the DF is coincident with bone growth in the tooth crypt. DF stem cells (DFSCs) have been shown to possess strong osteogenic capability. This study aims to determine the expression of BMP6 in DFSCs and to elucidate the role of BMP6 in the osteogenesis of DFSCs. DFSCs and their non-stem cell counterpart, DF cells (DFCs), were ob ...[more]

PMID: 24732882

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Project description:Bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation has been shown to occur through the canonical Wnt/?catenin pathway, whereas factors promoting canonical Wnt signaling in cementoblasts inhibit cell differentiation and promote cell proliferation in vitro. The aim of this study was to investigate whether putative precursor cells of cementoblasts, dental follicle cells (murine SVF4 cells), when stimulated with BMP2, would exhibit changes in genes/proteins associated with the Wnt/?-catenin pathway.SVF4 cells were stimulated with BMP2, and the following assays were carried out: (i) Wnt/?-catenin pathway activation assessed by western blotting, ?-catenin/transcription factor (TCF) reporter assays and expression of the lymphoid enhancer-binding factor-1 (Lef1), transcription factor 7 (Tcf7), Wnt inhibitor factor 1 (Wif1) and Axin2 (Axin2) genes; and (ii) cementoblast/osteoblast differentiation assessed by mineralization in vitro, and by the mRNA levels of runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), osteocalcin (Ocn) and bone sialoprotein (Bsp), determined by quantitative PCR after treatment with wingless-type MMTV integration site family, member 3A (WNT3A) and knockdown of ?-catenin.WNT3A induced ?-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt-responsive reporter, suggesting that the Wnt/?-catenin pathway functions in SVF4 cells. Activation of Wnt signaling with WNT3A suppressed BMP2-mediated induction of cementoblast/osteoblast maturation of SVF4 cells. However, ?-catenin knockdown showed that the BMP2-induced expression of cementoblast/osteoblast differentiation markers requires endogenous ?-catenin. WNT3A down-regulated transcripts for Runx2, Alp and Ocn in SVF4 cells compared with untreated cells. In contrast, BMP2 induction of Bsp transcripts occurred independently of Wnt/?-catenin signaling.These data suggest that stabilization of ?-catenin by WNT3A inhibits BMP2-mediated induction of cementoblast/osteoblast differentiation in SVF4 cells, although BMP2 requires endogenous Wnt/?-catenin signaling to promote cell maturation.

Project description:Bone morphogenetic protein-2 (BMP-2) is a growth factor used to stimulate bone regeneration in clinical applications. However, there are contradicting reports on the functionality of BMP-2 in human adipose stem cells (hASCs), which are frequently used in tissue engineering. In this study, we analyzed the effects of BMP-2 on SMAD1/5 signaling, proliferation, and differentiation in hASCs. Our results indicated that BMP-2 induced dose-dependent (25-100 ng/ml) activation of SMAD signaling. Furthermore, the cell proliferation analysis revealed that BMP-2 (100 ng/ml) consistently decreased the proliferation in all the cell lines studied. However, the analysis of the differentiation potential revealed that BMP-2 (100 ng/ml) exhibited a donor-dependent dual role, inducing both osteogenic and adipogenic differentiation in hASCs. The quantitative alkaline phosphatase (qALP) activity and mineralization levels were clearly enhanced in particular donor cell lines by BMP-2 stimulus. On the contrary, in other cell lines, qALP and mineralization levels were diminished and the lipid formation was enhanced. The current study also suggests that hASCs have accelerated biochemical responsiveness to BMP-2 stimulus in human serum-supplemented culture medium compared with fetal bovine serum. The production origin of the BMP-2 growth factor is also important for its response: BMP-2 produced in mammalian cells enhanced signaling and differentiation responses compared with BMP-2 produced in Escherichia coli. These results explain the existing contradiction in the reported BMP-2 studies and indicate the variability in the functional end mechanism of BMP-2-stimulated hASCs.This study examined how bone morphogenetic protein-2 (BMP-2) modulates the SMAD signaling mechanism and the proliferation and differentiation outcome of human adipose stem cells (hASCs) derived from several donors. The results indicate that BMP-2 triggers molecular SMAD signaling mechanisms in hASCs and regulates differentiation processes in human serum-culture conditions. Importantly, BMP-2 has dual activity, inducing osteogenic and adipogenic differentiation, subject to hASC donor line studied. These findings explain contradictory previous results and highlight the importance of further studies to understand how signaling pathways guide mesenchymal stem cell functions at the molecular level.

Dataset Information

Expression of bone morphogenetic protein-6 in dental follicle stem cells and its effect on osteogenic differentiation.

Publications

Expression of bone morphogenetic protein-6 in dental follicle stem cells and its effect on osteogenic differentiation.

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