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Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling.

Harada H, Kettunen P, Jung HS, Mustonen T, Wang YA, Thesleff I - J. Cell Biol. (1999)

Bottom Line: It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium.When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe.We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Programme, Institute of Biotechnology, Viikki Biocenter, University of Helsinki, 00014 Helsinki, Finland.

ABSTRACT
The continuously growing mouse incisor is an excellent model to analyze the mechanisms for stem cell lineage. We designed an organ culture method for the apical end of the incisor and analyzed the epithelial cell lineage by 5-bromo-2'-deoxyuridine and DiI labeling. Our results indicate that stem cells reside in the cervical loop epithelium consisting of a central core of stellate reticulum cells surrounded by a layer of basal epithelial cells, and that they give rise to transit-amplifying progeny differentiating into enamel forming ameloblasts. We identified slowly dividing cells among the Notch1-expressing stellate reticulum cells in specific locations near the basal epithelial cells expressing lunatic fringe, a secretory molecule modulating Notch signaling. It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium. Expression of Fgf-3 and Fgf-10 were restricted to the mesenchyme underlying the basal epithelial cells and the transit-amplifying cells expressing their receptors Fgfr1b and Fgfr2b. When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe. We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

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A model for the molecular mechanisms involved in the generation of the ameloblast cell lineage from stem cells. (a) Stem cell kinetics. The stem cell divides slowly and gives rise to one daughter cell remaining in the stem cell pool in the cervical loop, whereas the other daughter cell enters the zone of rapidly dividing inner enamel epithelial cells (transit-amplifying cell population). During rounds of divisions, these cells move toward the incisal direction and differentiate into ameloblasts forming enamel matrix. They are in close contact with dental mesenchyme expressing FGF-10, which stimulates the division of both stem cells and transit-amplifying cells (inner enamel epithelial cells), and FGF-3 stimulating division of transit-amplifying cells only. (b) Signaling pathways for cell fate specification in ameloblast cell lineage. Mesenchymal FGF-10 (green dots) stimulates lunatic fringe (blue dots) expression in the basal epithelium. The stem cells are located in the stellate reticulum expressing Notch1 (red stripes). Lunatic fringe modulates Notch signaling in the stem cells. When the daughter of a stem cell enters the zone of lunatic fringe expression in basal epithelium it will be incorporated to the ameloblast cell lineage interacting with adjacent mesenchymal cells. In the zone of differentiated cells (left), the Notch signaling pathway regulates interactions between ameloblasts expressing Serrate1 and stratum intermedium cells expressing Notch1. Abbreviations: a, ameloblast; be, basal epithelial cell; bm, basement membrane; d, dentin; e, enamel; iee, inner enamel epithelial cell; m, mesenchymal cell; o, odontoblast; si, stratum intermedium; and sr, stellate reticulum.
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Figure 10: A model for the molecular mechanisms involved in the generation of the ameloblast cell lineage from stem cells. (a) Stem cell kinetics. The stem cell divides slowly and gives rise to one daughter cell remaining in the stem cell pool in the cervical loop, whereas the other daughter cell enters the zone of rapidly dividing inner enamel epithelial cells (transit-amplifying cell population). During rounds of divisions, these cells move toward the incisal direction and differentiate into ameloblasts forming enamel matrix. They are in close contact with dental mesenchyme expressing FGF-10, which stimulates the division of both stem cells and transit-amplifying cells (inner enamel epithelial cells), and FGF-3 stimulating division of transit-amplifying cells only. (b) Signaling pathways for cell fate specification in ameloblast cell lineage. Mesenchymal FGF-10 (green dots) stimulates lunatic fringe (blue dots) expression in the basal epithelium. The stem cells are located in the stellate reticulum expressing Notch1 (red stripes). Lunatic fringe modulates Notch signaling in the stem cells. When the daughter of a stem cell enters the zone of lunatic fringe expression in basal epithelium it will be incorporated to the ameloblast cell lineage interacting with adjacent mesenchymal cells. In the zone of differentiated cells (left), the Notch signaling pathway regulates interactions between ameloblasts expressing Serrate1 and stratum intermedium cells expressing Notch1. Abbreviations: a, ameloblast; be, basal epithelial cell; bm, basement membrane; d, dentin; e, enamel; iee, inner enamel epithelial cell; m, mesenchymal cell; o, odontoblast; si, stratum intermedium; and sr, stellate reticulum.

Mentions: Our localization of the expression of Fgf-10 and Fgf-3, two signal molecules that we have recently identified as proliferative signals from mesenchyme to epithelium during early tooth morphogenesis (Kettunen, P., N. Itoh, and I. Thesleff, manuscript submitted for publication), suggested that they might function in the regulation of the continuous growth of the incisor epithelium. The expression of both Fgfs was restricted to the mesenchyme underlying the rapidly proliferating inner enamel epithelium. In addition, Fgf-10 expression extended more apically and surrounded the entire cervical loop. Furthermore, the FGF receptors that are known to bind these particular FGFs, namely the IIIb splice forms of FGFR1 and FGFR2 were expressed in the cervical loop epithelium, Fgfr1b mRNA being specifically intense in the basal epithelial cells facing the mesenchyme. These findings supported roles for FGF-3 and FGF-10 as signals mediating the effects of mesenchyme on epithelium, and our bead implantation experiments showed that FGF-10, in fact, stimulated proliferation in isolated cervical loop epithelium in vitro. It is apparent that they stimulated cell division in the transit-amplifying cell population in the cervical loop, and we also suggest that they stimulated proliferation of the stem cells (Fig. 10 a).


Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling.

Harada H, Kettunen P, Jung HS, Mustonen T, Wang YA, Thesleff I - J. Cell Biol. (1999)

A model for the molecular mechanisms involved in the generation of the ameloblast cell lineage from stem cells. (a) Stem cell kinetics. The stem cell divides slowly and gives rise to one daughter cell remaining in the stem cell pool in the cervical loop, whereas the other daughter cell enters the zone of rapidly dividing inner enamel epithelial cells (transit-amplifying cell population). During rounds of divisions, these cells move toward the incisal direction and differentiate into ameloblasts forming enamel matrix. They are in close contact with dental mesenchyme expressing FGF-10, which stimulates the division of both stem cells and transit-amplifying cells (inner enamel epithelial cells), and FGF-3 stimulating division of transit-amplifying cells only. (b) Signaling pathways for cell fate specification in ameloblast cell lineage. Mesenchymal FGF-10 (green dots) stimulates lunatic fringe (blue dots) expression in the basal epithelium. The stem cells are located in the stellate reticulum expressing Notch1 (red stripes). Lunatic fringe modulates Notch signaling in the stem cells. When the daughter of a stem cell enters the zone of lunatic fringe expression in basal epithelium it will be incorporated to the ameloblast cell lineage interacting with adjacent mesenchymal cells. In the zone of differentiated cells (left), the Notch signaling pathway regulates interactions between ameloblasts expressing Serrate1 and stratum intermedium cells expressing Notch1. Abbreviations: a, ameloblast; be, basal epithelial cell; bm, basement membrane; d, dentin; e, enamel; iee, inner enamel epithelial cell; m, mesenchymal cell; o, odontoblast; si, stratum intermedium; and sr, stellate reticulum.
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Related In: Results  -  Collection

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Figure 10: A model for the molecular mechanisms involved in the generation of the ameloblast cell lineage from stem cells. (a) Stem cell kinetics. The stem cell divides slowly and gives rise to one daughter cell remaining in the stem cell pool in the cervical loop, whereas the other daughter cell enters the zone of rapidly dividing inner enamel epithelial cells (transit-amplifying cell population). During rounds of divisions, these cells move toward the incisal direction and differentiate into ameloblasts forming enamel matrix. They are in close contact with dental mesenchyme expressing FGF-10, which stimulates the division of both stem cells and transit-amplifying cells (inner enamel epithelial cells), and FGF-3 stimulating division of transit-amplifying cells only. (b) Signaling pathways for cell fate specification in ameloblast cell lineage. Mesenchymal FGF-10 (green dots) stimulates lunatic fringe (blue dots) expression in the basal epithelium. The stem cells are located in the stellate reticulum expressing Notch1 (red stripes). Lunatic fringe modulates Notch signaling in the stem cells. When the daughter of a stem cell enters the zone of lunatic fringe expression in basal epithelium it will be incorporated to the ameloblast cell lineage interacting with adjacent mesenchymal cells. In the zone of differentiated cells (left), the Notch signaling pathway regulates interactions between ameloblasts expressing Serrate1 and stratum intermedium cells expressing Notch1. Abbreviations: a, ameloblast; be, basal epithelial cell; bm, basement membrane; d, dentin; e, enamel; iee, inner enamel epithelial cell; m, mesenchymal cell; o, odontoblast; si, stratum intermedium; and sr, stellate reticulum.
Mentions: Our localization of the expression of Fgf-10 and Fgf-3, two signal molecules that we have recently identified as proliferative signals from mesenchyme to epithelium during early tooth morphogenesis (Kettunen, P., N. Itoh, and I. Thesleff, manuscript submitted for publication), suggested that they might function in the regulation of the continuous growth of the incisor epithelium. The expression of both Fgfs was restricted to the mesenchyme underlying the rapidly proliferating inner enamel epithelium. In addition, Fgf-10 expression extended more apically and surrounded the entire cervical loop. Furthermore, the FGF receptors that are known to bind these particular FGFs, namely the IIIb splice forms of FGFR1 and FGFR2 were expressed in the cervical loop epithelium, Fgfr1b mRNA being specifically intense in the basal epithelial cells facing the mesenchyme. These findings supported roles for FGF-3 and FGF-10 as signals mediating the effects of mesenchyme on epithelium, and our bead implantation experiments showed that FGF-10, in fact, stimulated proliferation in isolated cervical loop epithelium in vitro. It is apparent that they stimulated cell division in the transit-amplifying cell population in the cervical loop, and we also suggest that they stimulated proliferation of the stem cells (Fig. 10 a).

Bottom Line: It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium.When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe.We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Programme, Institute of Biotechnology, Viikki Biocenter, University of Helsinki, 00014 Helsinki, Finland.

ABSTRACT
The continuously growing mouse incisor is an excellent model to analyze the mechanisms for stem cell lineage. We designed an organ culture method for the apical end of the incisor and analyzed the epithelial cell lineage by 5-bromo-2'-deoxyuridine and DiI labeling. Our results indicate that stem cells reside in the cervical loop epithelium consisting of a central core of stellate reticulum cells surrounded by a layer of basal epithelial cells, and that they give rise to transit-amplifying progeny differentiating into enamel forming ameloblasts. We identified slowly dividing cells among the Notch1-expressing stellate reticulum cells in specific locations near the basal epithelial cells expressing lunatic fringe, a secretory molecule modulating Notch signaling. It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium. Expression of Fgf-3 and Fgf-10 were restricted to the mesenchyme underlying the basal epithelial cells and the transit-amplifying cells expressing their receptors Fgfr1b and Fgfr2b. When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe. We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

Show MeSH