CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in the dental stem cell niche
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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.
KeywordsCXCR4/CXCL12 signal Tooth Dental stem cell niche Migration Proliferation
We are grateful to Dr. Stephanie Tsang (University of Illinois at Urbana-Champaign), Dr. Myung-Eun Shin (Duke University Medical Center), and Ms. Yanzhen Li, M.A. (University of North Carolina) for critical discussions; to Mr. Naoyuki Tamaki (IBM Global Services Japan Solution and Services Company ISOL) for technical support in generating beautiful figures; Dr. Yuko Suzuki (Health Sciences University of Hokkaido) for excellent suggestions and for providing materials. This work was supported by JSPS KAKENHI Grant Numbers 19791342, 15K20358 to Y-T. T. We are also grateful for the funding for this study provided by the Chemistry-Biology Interface Training Program NIH NIGMS T32GM070421 (SRC) as well as the Chemical and Biomolecular Engineering Dept. (BAH), and the Institute for Genomic Biology (BAH) at the University of Illinois at Urbana-Champaign.
Conflicts of interest
The authors indicate no potential conflicts of interest.
Tamaki Yokohama-Tamaki: conception and design, manuscript writing, collection and assembly of all data. Otsu Keishi: provision of materials (mHAT9a cells) and data analysis. Hidemitsu Harada: provision of materials (mHAT9a cells). Nobuko Obara: construction of CXCL12 mRNA probe. Kazuharu Irie and Shunichi Shibata: data analysis and interpretation of histology. Akiyoshi Taniguchi: data analysis and interpretation of real-time PCR. Takashi Nagasawa, Kazunari Aoki: provision of materials (CXCR4 and CXCL12 knockout mice). Steven R. Caliari: data analysis and interpretation of real-time PCR and transwell cell migration assays. Daniel W. Weisgerber: data analysis and interpretation of alamarBlue assays. Brendan A.C. Harley: provision of study material, data analysis and interpretation, financial support, final approval of manuscript.
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