Foxc2 and BMP2 Induce Osteogenic/Odontogenic Differentiation and Mineralization of Human Stem Cells from Apical Papilla

Wen, Zheng; Zhang, Xiaolei; Li, Junyuan; Zheng, Jianfei; Hu, Xiaoli; Xu, Meng; Mao, Xueli

doi:10.1155/2018/2363917

Cited by 16 publications

(26 citation statements)

References 33 publications

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“…On the contrary, frequent mitotic events can be observed in cells transfected with FOXC2 native sequence, demonstrating that the transcription factor is involved in cell proliferation. This result agrees with a great deal of previously reported evidence attesting the key role of FOXC2 in promoting the proliferation of tumor cells in vitro and in vivo [36][37][38]. It has also been shown that wild type FOXC2 can induce expression of several cell cycle regulators, including cyclin-dependent kinase 1 (CDK1) [19].…”

Section: Discussionsupporting

confidence: 92%

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

Tavian

Missaglia

Michelini

et al. 2020

IJMS

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FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death.

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Section: Discussionsupporting

confidence: 92%

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

Tavian

Missaglia

Michelini

et al. 2020

IJMS

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“…BMP2, a member of the TGF-β family of proteins, contributes to odontogenic differentiation in DPSCs [18, 19]. Consistent with KEGG pathway data, BMP2, BMPR1, and phosphorylated Smad1/5/9 amounts were significantly increased in DPSCs incubated in Mg 2+ -enriched odontogenic media.…”

Section: Discussionmentioning

confidence: 60%

“…As reported previously, BMP2 is a TGF-β family member controlling odontogenic differentiation of stem cells [18, 19]. To verify the above KEGG pathway data, we performed Western blot to determine whether BMP2/Smads signaling is activated by high extracellular Mg 2+ .…”

Section: Resultsmentioning

confidence: 82%

Magnesium-enriched microenvironment promotes odontogenic differentiation in human dental pulp stem cells by activating ERK/BMP2/Smads signaling

Kong

Zhong

et al. 2019

Stem Cell Res Ther

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Background: Magnesium (Mg 2+)-enriched microenvironment promotes odontogenic differentiation in human dental pulp stem cells (DPSCs), but the regulatory mechanisms remain undefined. The aim of this work was to assess magnesium's function in the above process and to explore the associated signaling pathway. Methods: DPSCs underwent culture in odontogenic medium with the addition of 0, 1, 5, or 10 mM MgCl 2. Intracellular Mg 2+ levels in DPSCs were evaluated flow cytometrically using Mag-Fluo-4-AM. Mg 2+-entry was inhibited by TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB). RNA-Sequencing was carried out for assessing transcriptome alterations in DPSCs during odontogenic differentiation associated with high extracellular Mg 2+. KEGG pathway analysis was performed to determine pathways related to the retrieved differentially expressed genes (DEGs). Immunoblot was performed for assessing magnesium's role and exploring ERK/BMP2/Smads signaling. Results: Mg 2+-enriched microenvironment promoted odontogenic differentiation in DPSCs via intracellular Mg 2+ increase. Consistently, the positive effect of high extracellular Mg 2+ on odontogenic differentiation in DPSCs was blocked by 2-APB, which reduced Mg 2+ entry. RNA-sequencing identified 734 DEGs related to odontogenic differentiation in DPSCs in the presence of high extracellular Mg 2+. These DEGs participated in many cascades such as MAPK and TGF-β pathways. Consistently, ERK and BMP2/Smads pathways were activated in DPSCs treated with high extracellular Mg 2+. In agreement, ERK signaling inhibition by U0126 blunted the effect of high extracellular Mg 2+ on mineralization and odontogenic differentiation in DPSCs. Interestingly, BMP2, BMPR1, and phosphorylated Smad1/5/9 were significantly decreased by U0126, indicating that BMP2/Smads acted as downstream of ERK. Conclusions: Mg 2+-enriched microenvironment promotes odontogenic differentiation in DPSCs by activating ERK/ BMP2/Smads signaling via intracellular Mg 2+ increase. This study revealed that Mg 2+-enriched microenvironment could be used as a new strategy for dental pulp regeneration.

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“…Furthermore, there are a large number of studies investigating the influence of molecules on the directed differentiation of SCAPs. The osteo/odontogenic differentiation of SCAPs can be promoted by forkhead c2 [37], bone morphogenetic protein 2 ( BMP2) [37–39], BMP9 [32, 40], SH3 and multiple ankyrin repeat domains 2 [25], GATA binding protein 4 [41], 17 β -estradiol [28], nuclear factor I-C [42, 43], secreted frizzled-related protein 2 (SFRP2) [44, 45], WD repeat domain 63 [34], insulin-like growth factor-1 [30, 46], recombinant human plasminogen activator inhibitor-1 [26], Rac1 gene [31], early growth response gene 1 [47], sirtuin 1 [48], potassium phosphate monobasic [49], canonical NF-kappaB signaling pathway [27], wnt/ β -catenin signaling [50], and some dentin-derived proteins [51]. By contrast, microRNA hsa-let-7b [52] and sonic hedgehog signaling [53] are able to inhibit this differentiation of SCAPs.…”

Section: Multilineage Differentiationmentioning

confidence: 99%

Stem Cells from the Apical Papilla: A Promising Source for Stem Cell-Based Therapy

Kang

Fan

Deng

et al. 2019

BioMed Research International

113

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Stem cells are biological cells that can self-renew and can differentiate into multiple cell lineages. Stem cell-based therapy is emerging as a promising alternative therapeutic option for various disorders. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are isolated from various tissues and can be used as an alternative to embryonic stem cells. Stem cells from the apical papilla (SCAPs) are a novel population of MSCs residing in the apical papilla of immature permanent teeth. SCAPs present the characteristics of expression of MSCs markers, self-renewal, proliferation, migration, differentiation, and immunosuppression, which support the application of SCAPs in stem cell-based therapy, including the immunotherapy and the regeneration of dental tissues, bone, neural, and vascular tissues. In view of these properties and therapeutic potential, SCAPs can be considered as promising candidates for stem cell-based therapy. Thus the aim of our review was to summarize the current knowledge of SCAPs considering isolation, characterization, and multilineage differentiation. The prospects for their use in stem cell-based therapy were also discussed.

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Foxc2 and BMP2 Induce Osteogenic/Odontogenic Differentiation and Mineralization of Human Stem Cells from Apical Papilla

Cited by 16 publications

References 33 publications

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

Magnesium-enriched microenvironment promotes odontogenic differentiation in human dental pulp stem cells by activating ERK/BMP2/Smads signaling

Stem Cells from the Apical Papilla: A Promising Source for Stem Cell-Based Therapy

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