title: CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in the dental stem cell niche.
abstract: Dental stem cells are located at the proximal ends of rodent incisors. These stem cells reside in the dental epithelial stem cell niche, termed the apical bud. We focused on identifying critical features of a chemotactic signal in the niche. Here, we report that CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in dental stem cell niche cells. We report cells in the apical bud express CXCR4 mRNA at high levels while expression is restricted in the basal epithelium (BE) and transit-amplifying (TA) cell regions. Furthermore, the CXCL12 ligand is present in mesenchymal cells adjacent to the apical bud. We then performed gain- and loss-of-function analyses to better elucidate the role of CXCR4 and CXCL12. CXCR4-deficient mice contain epithelial cell aggregates, while cell proliferation in mutant incisors was also significantly reduced. We demonstrate in vitro that dental epithelial cells migrate toward sources of CXCL12, whereas knocking down CXCR4 impaired motility and resulted in formation of dense cell colonies. These results suggest that CXCR4 expression may be critical for activation of enamel progenitor cell division and that CXCR4/CXCL12 signaling may control movement of epithelial progenitors from the dental stem cell niche.
authors.affiliation: Division of Histology, Department of Oral Growth and Development, School of Dentistry, Health sciences University of Hokkaido, Hokkaido, Japan. ttamaki.mfa@tmd.ac.jp.|Maxillofacial Anatomy, Department of Maxillofacial Biology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. ttamaki.mfa@tmd.ac.jp.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Yokohama-Tamaki
authors.affiliation: Division of Oral Histology and Developmental Biology, School of Dentistry, Iwate Medical University, Iwate, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Otsu
authors.affiliation: Division of Oral Histology and Developmental Biology, School of Dentistry, Iwate Medical University, Iwate, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Harada
authors.affiliation: Maxillofacial Anatomy, Department of Maxillofacial Biology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Division of Histology, Department of Oral Growth and Development, School of Dentistry, Health sciences University of Hokkaido, Hokkaido, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Obara
authors.affiliation: Division of Histology, Department of Oral Growth and Development, School of Dentistry, Health sciences University of Hokkaido, Hokkaido, Japan.
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Irie
authors.affiliation: Biomaterials Center, National Institute for Materials Science, Ibaraki, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Caliari
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Weisgerber
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA. bharley@illinois.edu.
authors.forename: Brendan A C
authors.initials: BA
authors.lastname: Harley
mesh_terms: D000818:Animals; D002449:Cell Aggregation; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D054377:Chemokine CXCL12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003743:Dental Enamel / Q000166:cytology*; D004847:Epithelial Cells; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007180:Incisor / Q000166:cytology / Q000196:embryology; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4
keywords: CXCR4/CXCL12 signal; Dental stem cell niche; Migration; Proliferation; Tooth