Abstract
Epithelial-mesenchymal interactions regulate the growth and morphogenesis of ectodermal organs such as teeth. Dental pulp stem cells (DPSCs) are a part of dental mesenchyme, derived from the cranial neural crest, and differentiate into dentin forming odontoblasts. However, the interactions between DPSCs and epithelium have not been clearly elucidated. In this study, we established a mouse dental pulp stem cell line (SP) comprised of enriched side population cells that displayed a multipotent capacity to differentiate into odontogenic, osteogenic, adipogenic, and neurogenic cells. We also analyzed the interactions between SP cells and cells from the rat dental epithelial SF2 line. When cultured with SF2 cells, SP cells differentiated into odontoblasts that expressed dentin sialophosphoprotein. This differentiation was regulated by BMP2 and BMP4, and inhibited by the BMP antagonist Noggin. We also found that mouse iPS cells cultured with mitomycin C-treated SF2-24 cells displayed an epithelial cell-like morphology. Those cells expressed the epithelial cell markers p63 and cytokeratin-14, and the ameloblast markers ameloblastin and enamelin, whereas they did not express the endodermal cell marker Gata6 or mesodermal cell marker brachyury. This is the first report of differentiation of iPS cells into ameloblasts via interactions with dental epithelium. Co-culturing with dental epithelial cells appears to induce stem cell differentiation that favors an odontogenic cell fate, which may be a useful approach for tooth bioengineering strategies.
Highlights
The role of dental epithelium in stem cell differentiation has not been clearly elucidated
Side population (SP) cells differentiated into odontoblasts by epithelial BMP4, whereas induced pluripotent stem (iPS) cells differentiated into ameloblasts when cultured with dental epithelium
Cell sorting was repeated three times and SP cells were enriched from about 0.9% to 82.3% in the gated area (Fig. 1A). This SP cell line showed high expression levels of the stem cell markers Sca-1 and Oct3/4 when compared with the majority population (MP) cells, which was comprised of a greater number dental papilla cells in various differentiation stages (Fig. 1B)
Summary
The role of dental epithelium in stem cell differentiation has not been clearly elucidated. Results: SP cells differentiated into odontoblasts by epithelial BMP4, whereas iPS cells differentiated into ameloblasts when cultured with dental epithelium. Dental pulp stem cells (DPSCs) are a part of dental mesenchyme, derived from the cranial neural crest, and differentiate into dentin forming odontoblasts. At later stages of tooth development, the basement membrane components disappear and odontogenic cells begin to secrete a variety of tooth-specific extracellular matrices that give rise to layers of enamel and dentin, produced by epithelial-derived ameloblasts and mesenchymal-derived odontoblasts, respectively. In tooth germ development, undifferentiated neural crest-derived MSCs interact with dental epithelium and differentiate into dentin matrix-secreting odontoblasts. Mouse iPS cells differentiated into Ambn-expressing dental epithelium when cultured with dental epithelial cells These undifferentiated stem cells can be induced to an odontogenic cell fate when co-cultured with dental epithelial cells. These findings may be useful for analysis of dental cell differentiation in vitro and for procurement of odontogenic cells for use in regenerative medicine
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