The expansion of progenitor cells during organogenesis requires c-Kit/Fgfr2b-dependent transcription factor expression

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIDCR	STEMCELL-5

* FARE Award Winner

Authors

• I Lombaert
• S Abrams
• M Hoffman

Abstract

Co-irradiation of salivary glands (SMG) often occurs in head-and-neck cancer patients, leading to a permanent loss of saliva production. Transplantation of c-Kit+ SMG stem/progenitor cells regenerated irradiated mouse SMGs. Therefore, we hypothesize that c-Kit signaling is required for the maintenance/expansion of SMG progenitor cells. During SMG development, epithelial end buds express c-Kit whereas its ligand, stem cell factor (SCF), is produced by the mesenchyme and epithelia. Importantly, in the absence of Fgf10 or Fgfr2b the SMG does not develop. We demonstrate that Fgf10/Fgfr2b signaling is essential for the proliferation of c-Kit+ progenitors by regulating SCF and c-Kit. Knockdown of c-Kit using siRNA significantly downregulated transcription factors (TFs) downstream of Fgf10/Fgfr2b-MAPK signaling in the SMG: Etv4, Etv5, c-Myc and Sox10, which are involved in progenitor cell maintenance/self-renewal. Exogenous SCF did not regulate these TFs, however, stimulation of Fgf10-treated epithelium with SCF resulted in an increase in gene expression. Addition of SCF to Fgf10-cultured epithelia also increased the number of Keratin14 (K14)-expressing cells, which are a progenitor population co-expressing Sox10. In summary, Fgf10/Fgr2b signaling maintains c-Kit progenitor cells during development by regulating SCF and c-Kit expression. Subsequently, SCF/c-Kit expands K14+ progenitors by enhancing gene expression of cMyc, Sox10, Etv4 and Etv5.

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