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Article ; Online: A Member-Centric Association.

Nör, J E

2021 Volume 100, Issue 13, Page(s) 1427–1428

MeSH term(s)	Leadership
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/00220345211048482
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Article ; Online: Crosstalk between cancer stem cells and the tumor microenvironment drives progression of premalignant oral epithelium.

Polverini, Peter J / Nör, Felipe / Nör, Jacques E

Frontiers in oral health

2023 Volume 3, Page(s) 1095842

Abstract: Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial ...

Abstract	Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial stem cells acquire the CSC phenotype following exposure to environmental or infectious mutagens and are responsible for promoting the malignant transformation of premalignant (dysplastic) epithelium. CSC further contribute to the progression of dysplasia by activating signaling pathways through crosstalk with various cell populations in the tumor microenvironment. Two cell types, tumor-associated macrophages (TAM) and vascular endothelial cells (EC) nurture CSC development, support CSC stemness, and contribute to tumor progression. Despite mounting evidence implicating CSC in the initiation and progression of dysplastic oral epithelium to squamous cell carcinoma (SCC), the molecular mechanisms underlying these synergistic biological processes remain unclear. This review will examine the mechanisms that underlie the transformation of normal epithelial stem cells into CSC and the mechanistic link between CSC, TAM, and EC in the growth and the malignant conversation of dysplastic oral epithelium.
Language	English
Publishing date	2023-01-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2673-4842
ISSN (online)	2673-4842
DOI	10.3389/froh.2022.1095842
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Article ; Online: Injectable Tissue-Specific Hydrogel System for Pulp-Dentin Regeneration.

Han, Y / Xu, J / Chopra, H / Zhang, Z / Dubey, N / Dissanayaka, W L / Nör, J E / Bottino, M C

Journal of dental research

2024 Volume 103, Issue 4, Page(s) 398–408

Abstract: The quest for finding a suitable scaffold system that supports cell survival and function and, ultimately, the regeneration of the pulp-dentin complex remains challenging. Herein, we hypothesized that dental pulp stem cells (DPSCs) encapsulated in a ... ...

Abstract	The quest for finding a suitable scaffold system that supports cell survival and function and, ultimately, the regeneration of the pulp-dentin complex remains challenging. Herein, we hypothesized that dental pulp stem cells (DPSCs) encapsulated in a collagen-based hydrogel with varying stiffness would regenerate functional dental pulp and dentin when concentrically injected into the tooth slices. Collagen hydrogels with concentrations of 3 mg/mL (Col3) and 10 mg/mL (Col10) were prepared, and their stiffness and microstructure were assessed using a rheometer and scanning electron microscopy, respectively. DPSCs were then encapsulated in the hydrogels, and their viability and differentiation capacity toward endothelial and odontogenic lineages were evaluated using live/dead assay and quantitative real-time polymerase chain reaction. For in vivo experiments, DPSC-encapsulated collagen hydrogels with different stiffness, with or without growth factors, were injected into pulp chambers of dentin tooth slices and implanted subcutaneously in severe combined immunodeficient (SCID) mice. Specifically, vascular endothelial growth factor (VEGF [50 ng/mL]) was loaded into Col3 and bone morphogenetic protein (BMP2 [50 ng/mL]) into Col10. Pulp-dentin regeneration was evaluated by histological and immunofluorescence staining. Data were analyzed using 1-way or 2-way analysis of variance accordingly (α = 0.05). Rheology and microscopy data revealed that Col10 had a stiffness of 8,142 Pa with a more condensed and less porous structure, whereas Col3 had a stiffness of 735 Pa with a loose microstructure. Furthermore, both Col3 and Col10 supported DPSCs' survival. Quantitative polymerase chain reaction showed Col3 promoted significantly higher von Willebrand factor (VWF) and CD31 expression after 7 and 14 d under endothelial differentiation conditions (
MeSH term(s)	Mice ; Animals ; Cells, Cultured ; Vascular Endothelial Growth Factor A/metabolism ; von Willebrand Factor/metabolism ; Hydrogels/metabolism ; Mice, SCID ; Collagen/metabolism ; Cell Differentiation ; Intercellular Signaling Peptides and Proteins/metabolism ; Dentin ; Dental Pulp ; Cell Proliferation
Chemical Substances	Vascular Endothelial Growth Factor A ; von Willebrand Factor ; Hydrogels ; Collagen (9007-34-5) ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/00220345241226649
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Article ; Online: Oral-Gut-Estrobolome Axis May Exert a Selective Impact on Oral Cancer.

Tatullo, M / Nor, J / Orrù, G / Piattelli, A / Cascardi, E / Spagnuolo, G

Journal of dental research

2024 Volume 103, Issue 5, Page(s) 461–466

Abstract: ... they can modulate the pathological profile of some bacteria, somewhere associated with neoplastic processes (i.e., ...

Abstract	A subset of bacterial species that holds genes encoding for β-glucuronidase and β-galactosidase, enzymes involved in the metabolism of conjugated estrogens, is called the "estrobolome." There is an emerging interest embracing this concept, as it may exert a selective impact on a number of pathologies, including oral cancer. Although the estrobolome bacteria are typically part of the gut microbiota, recent experimental pieces of evidence have suggested a crosstalk among oral and gut microbiota. In fact, several oral bacterial species are well represented also in the gut microbiota, and these microbes can effectively induce the estrobolome activation. The main pathways used for activating the estrobolome are based on the induction of the expression patterns for 2 bacterial enzymes: β-glucuronidase and aromatase, both involved in the increase of estrogen released in the bloodstream and consequently in the salivary compartment. Mechanistically, high estrogen availability in saliva is responsible for an increase in oral cancer risk for different reasons: briefly, 1) estrogens directly exert biological and metabolic effects on oral mucosa cells; 2) they can modulate the pathological profile of some bacteria, somewhere associated with neoplastic processes (i.e.,
MeSH term(s)	Humans ; Gastrointestinal Microbiome ; Mouth Neoplasms ; Estrogens/metabolism ; Mouth/microbiology ; Glucuronidase/metabolism ; Saliva/microbiology ; Saliva/metabolism ; beta-Galactosidase/metabolism
Chemical Substances	Estrogens ; Glucuronidase (EC 3.2.1.31) ; beta-Galactosidase (EC 3.2.1.23)
Language	English
Publishing date	2024-04-07
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/00220345241236125
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Article ; Online: Head and Neck Cancer in the New Era of Precision Medicine.

Nör, J E / Gutkind, J S

Journal of dental research

2018 Volume 97, Issue 6, Page(s) 601–602

MeSH term(s)	Carcinoma, Squamous Cell/diagnosis ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/therapy ; Head and Neck Neoplasms/diagnosis ; Head and Neck Neoplasms/genetics ; Head and Neck Neoplasms/therapy ; Humans ; Precision Medicine
Language	English
Publishing date	2018-07-02
Publishing country	United States
Document type	Editorial
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/0022034518772278
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Article ; Online: VEGFR1 primes a unique cohort of dental pulp stem cells for vasculogenic differentiation.

Bergamo, M T / Zhang, Z / Oliveira, T M / Nör, J E

European cells & materials

2021 Volume 41, Page(s) 332–344

Abstract: ... for vascular endothelial growth factor receptor 1 (VEGFR1) and exposed to vasculogenic differentiation medium, i.e ... anti-human VEGF antibody (bevacizumab; Genentech). In addition, sorted SHED (i.e., VEGFR1high or ...

Abstract	Dental pulp stem cells (DPSCs) constitute a unique group of cells endowed with multipotency, self-renewal, and capacity to regenerate the dental pulp tissue. While much has been learned about these cells in recent years, it is still unclear if each DPSC is multipotent or if unique sub-populations of DPSCs are "primed" to undergo specific differentiation paths. The purpose of the present study was to define whether a sub-population of DPSCs was uniquely primed to undergo vasculogenic differentiation. Permanent-tooth DPSCs or stem cells from human exfoliated deciduous teeth (SHED) were flow-sorted for vascular endothelial growth factor receptor 1 (VEGFR1) and exposed to vasculogenic differentiation medium, i.e., Microvascular-Endothelial-Cell-Growth-Medium-2-BulletKit™ supplemented with 50 ng/mL rhVEGF165 in the presence of 0 or 25 μg/mL anti-human VEGF antibody (bevacizumab; Genentech). In addition, sorted SHED (i.e., VEGFR1high or VEGFR1low) were seeded in biodegradable scaffolds and transplanted into the subcutaneous space of immunodeficient mice. Despite proliferating at a similar rate, VEGFR1high generated more in vitro sprouts than VEGFR1low cells (p < 0.05). Blockade of VEGF signaling with bevacizumab inhibited VEGFR1high-derived sprouts, demonstrating specificity of responses. Similarly, VEGFR1high SHED generated more blood vessels when transplanted into murine hosts than VEGFR1low cells (p < 0.05). Collectively, these data demonstrated that DPSCs contain a unique sub-population of cells defined by high VEGFR1 expression that are primed to differentiate into vascular endothelial cells. These data raise the possibility of purifying stem cells with high vasculogenic potential for regeneration of vascularized tissues or for vascular engineering in the treatment of ischemic conditions.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Cell Proliferation/physiology ; Cells, Cultured ; Dental Pulp/metabolism ; Endothelial Cells/metabolism ; Humans ; Mice ; Regeneration/physiology ; Signal Transduction/physiology ; Stem Cells/metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism
Chemical Substances	Vascular Endothelial Growth Factor Receptor-1 (EC 2.7.10.1)
Language	English
Publishing date	2021-03-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2046669-9
ISSN	1473-2262 ; 1473-2262
ISSN (online)	1473-2262
ISSN	1473-2262
DOI	10.22203/eCM.v041a21
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Article ; Online: Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication.

Fujii, Shinsuke / Hasegawa, Kana / Maehara, Takashi / Kurppa, Kari J / Heikinheimo, Kristiina / Warner, Kristy A / Maruyama, Satoshi / Tajiri, Yudai / Nör, Jacques E / Tanuma, Jun-Ichi / Kawano, Shintaro / Kiyoshima, Tamotsu

Pathology, research and practice

2024 Volume 254, Page(s) 155148

Abstract: Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still ... ...

Abstract	Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.
MeSH term(s)	Humans ; Carcinoma, Adenoid Cystic/pathology ; beta Catenin/metabolism ; Catenins/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Semaphorin-3A ; Neoplasm Recurrence, Local ; Salivary Gland Neoplasms/pathology ; Wnt Signaling Pathway ; Proto-Oncogene Proteins c-kit/metabolism
Chemical Substances	beta Catenin ; Catenins ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Semaphorin-3A ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
Language	English
Publishing date	2024-01-20
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391889-0
ISSN	1618-0631 ; 0344-0338
ISSN (online)	1618-0631
ISSN	0344-0338
DOI	10.1016/j.prp.2024.155148
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Article ; Online: Pulpbow: A Method to Study the Vasculogenic Potential of Mesenchymal Stem Cells from the Dental Pulp.

Mantesso, Andrea / Zhang, Zhaocheng / Warner, Kristy A / Herzog, Alexandra E / Pulianmackal, Ajai J / Nör, Jacques E

Cells

2021 Volume 10, Issue 11

Abstract: Understanding how Mesenchymal Stem Cells (MSCs) form blood vessels is critical for creating mechanism-based approaches for the therapeutic use of these cells. In addition, understanding the determinants and factors involved in lineage hierarchy is ... ...

Abstract	Understanding how Mesenchymal Stem Cells (MSCs) form blood vessels is critical for creating mechanism-based approaches for the therapeutic use of these cells. In addition, understanding the determinants and factors involved in lineage hierarchy is fundamental to creating accurate and reliable techniques for the study of stem cells in tissue engineering and repair. Dental Pulp Stem Cells (DPSC) from permanent teeth and Stem cells from Human Exfoliated Deciduous teeth (SHED) are particularly interesting sources for tissue engineering as they are easily accessible and expandable. Previously, we have shown that DPSCs and SHEDs can differentiate into endothelial cells and form functional blood vessels through vasculogenesis. Here, we described how we created the "pulpbow" (pulp + rainbow), a multicolor tag experimental model that is stable, permanent, unique to each cell and passed through generations. We used the pulpbow to understand how dental pulp stem cells contributed to blood vessel formation in 3D models in in vitro and ex vivo live cell tracking, and in vivo transplantation assays. Simultaneous tracking of cells during sprout formation revealed that no single multicolor-tagged cell was more prone to vasculogenesis. During this process, there was intense cell motility with minimal proliferation in early time points. In later stages, when the availability of undifferentiated cells around the forming sprout decreased, there was local clonal proliferation mediated by proximity. These results unveiled that the vasculogenesis process mediated by dental pulp stem cells is dynamic and proximity to the sprouting area is critical for cell fate decisions.
MeSH term(s)	Animals ; Cell Culture Techniques/methods ; Color ; Dental Pulp/cytology ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; Mice, Inbred C57BL ; Mice, SCID ; Neovascularization, Physiologic ; Time Factors ; Mice
Language	English
Publishing date	2021-10-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10112804
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Article ; Online: Role of Heparan Sulfate in Vasculogenesis of Dental Pulp Stem Cells.

Li, A / Sasaki, J I / Inubushi, T / Abe, G L / Nör, J E / Yamashiro, T / Imazato, S

Journal of dental research

2022 Volume 102, Issue 2, Page(s) 207–216

Abstract: Dental pulp stem cells (DPSCs) can differentiate into vascular endothelial cells and display sprouting ability. During this process, DPSC responses to the extracellular microenvironment and cell-extracellular matrix interactions are critical in ... ...

Abstract	Dental pulp stem cells (DPSCs) can differentiate into vascular endothelial cells and display sprouting ability. During this process, DPSC responses to the extracellular microenvironment and cell-extracellular matrix interactions are critical in regulating their ultimate cell fate. Heparan sulfate (HS) glycosaminoglycan, a major component of extracellular matrix, plays important roles in various biological cell activities by interacting with growth factors and relative receptors. However, the regulatory function of HS on vasculogenesis of mesenchymal stem cells remains unclear. The objective of this study was to investigate the role of HS in endothelial differentiation and vasculogenesis of DPSCs. Our results show that an HS antagonist suppressed the proliferation and sprouting ability of DPSCs undergoing endothelial differentiation. Furthermore, expression of proangiogenic markers significantly declined with increasing dosages of the HS antagonist; in contrast, expression of stemness marker increased. Silencing of exostosin 1 (EXT1), a crucial glycosyltransferase for HS biosynthesis, in DPSCs using a short hairpin RNA significantly altered their gene expression profile. In addition,
MeSH term(s)	Humans ; Animals ; Mice ; Dental Pulp ; Endothelial Cells ; Regeneration ; Cell Differentiation/physiology ; Stem Cells/physiology ; Heparitin Sulfate ; Cell Proliferation ; Cells, Cultured
Chemical Substances	Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/00220345221130682
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Article ; Online: Craniofacial Stem Cells in Health and Disease.

Klein, O D / Nör, J E

Journal of dental research

2015 Volume 94, Issue 11, Page(s) 1485–1486

MeSH term(s)	Humans ; Stem Cell Transplantation ; Stem Cells/physiology ; Stomatognathic Diseases/therapy
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	80207-4
ISSN	1544-0591 ; 0022-0345
ISSN (online)	1544-0591
ISSN	0022-0345
DOI	10.1177/0022034515608368
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