Abstract
Mouse incisors grow continuously throughout life. This growth is supported by the division of dental epithelial stem cells that reside in the cervical loop region. Little is known about the maintenance and regulatory mechanisms of dental epithelial stem cells. In the present study, we investigated how transforming growth factor β (TGF-β) signaling-mediated mesenchymal-epithelial cell interactions control dental epithelial stem cells. We designed two approaches using incisor organ culture and bromodeoxyuridine (BrdU) pulse-chase experiments to identify and evaluate stem cell functions. We show that the loss of the TGF-β type I receptor (Alk5) in the cranial neural crest-derived dental mesenchyme severely affects the proliferation of TA (transit-amplifying) cells and the maintenance of dental epithelial stem cells. Incisors of Wnt1-Cre; Alk5(fl/fl) mice lost their ability to continue to grow in vitro. The number of BrdU label-retaining cells (LRCs) was dramatically reduced in Alk5 mutant mice. Fgf10, Fgf3, and Fgf9 signals in the dental mesenchyme were downregulated in Wnt1-Cre; Alk5(fl/fl) incisors. Strikingly, the addition of exogenous fibroblast growth factor 10 (FGF10) into cultured incisors rescued dental epithelial stem cells in Wnt1-Cre; Alk5(fl/fl) mice. Therefore, we propose that Alk5 functions upstream of Fgf10 to regulate TA cell proliferation and stem cell maintenance and that this signaling mechanism is crucial for stem cell-mediated tooth regeneration.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activating Transcription Factor 2 / genetics
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Animals
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Bromodeoxyuridine
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Cell Differentiation
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Cell Proliferation
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Epithelial Cells / cytology
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Epithelial Cells / physiology*
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Fibroblast Growth Factor 10 / genetics
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Fibroblast Growth Factor 10 / metabolism*
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Fibroblast Growth Factor 10 / pharmacology
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Fibroblast Growth Factor 3 / genetics
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Fibroblast Growth Factor 3 / metabolism
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Fibroblast Growth Factor 9 / genetics
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Fibroblast Growth Factor 9 / metabolism
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Genotype
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Incisor / cytology*
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Incisor / growth & development
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Mesoderm / metabolism
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Mice
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Mice, Transgenic
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Organ Culture Techniques
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Peptide Fragments
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Polymerase Chain Reaction
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / deficiency
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction
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Stem Cells / cytology
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Stem Cells / physiology*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Wnt1 Protein / genetics
Substances
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154N-5 peptide
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Activating Transcription Factor 2
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Atf2 protein, mouse
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Fgf3 protein, mouse
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Fgf9 protein, mouse
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Fibroblast Growth Factor 10
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Fibroblast Growth Factor 3
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Fibroblast Growth Factor 9
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Peptide Fragments
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Wnt1 Protein
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Wnt1 protein, mouse
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Tgfbr1 protein, mouse
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Bromodeoxyuridine