Fibroblast Growth Factor Type 2 Signaling Is Critical for DNA Repair in Human Keratinocyte Stem Cells

• Published in: Stem cells (Dayton, Ohio) Vol. 28; no. 9; pp. 1639 - 1648
• Main Authors: Harfouche, Ghida, Vaigot, Pierre, Rachidi, Walid, Rigaud, Odile, Moratille, Sandra, Marie, Mélanie, Lemaitre, Gilles, Fortunel, Nicolas O., Martin, Michèle T.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2010
• Subjects: Antibodies, Monoclonal - pharmacology; Butadienes - pharmacology; Cell Cycle; Cells, Cultured; Chromatin Assembly and Disassembly; Comet Assay; DNA Breaks, Double-Stranded; DNA Breaks, Single-Stranded; DNA Repair; FGF2; Fibroblast Growth Factor 2 - antagonists & inhibitors; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Gene Expression Profiling; Gene Regulatory Networks; Genomic Instability; Histones - metabolism; Human skin; Humans; Keratinocyte; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - radiation effects; Nitriles - pharmacology; Phosphorylation; Progenitors; Protein Kinase Inhibitors - pharmacology; Recombinant Proteins - metabolism; Serine; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - radiation effects; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - radiation effects; Time Factors; Tissue-Specific Stem Cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.485

Tissue stem cells must be endowed with superior maintenance and repair systems to ensure genomic stability over multiple generations, which would be less necessary in more differentiated cells. We previously reported that human keratinocyte stem cells were more resistant to ionizing radiation toxicity than their direct progeny, the keratinocyte progenitor cells. In the present study we addressed the mechanisms underlying this difference. Investigations of DNA repair showed that both single and double DNA strand breaks were repaired more rapidly and more efficiently in stem cells than in progenitors. As cell signaling is a key regulatory step in the management of DNA damage, a gene profiling study was performed. Data revealed that several genes of the fibroblast growth factor type 2 (FGF2) signaling pathway were induced by DNA damage in stem cells and not in progenitors. Furthermore, an increased content of the FGF2 protein was found in irradiated stem cells, both for the secreted and the cellular forms of the protein. To examine the role of endogenous FGF2 in DNA repair, stem cells were exposed to FGF2 pathway inhibitors. Blocking the FGF2 receptor (FGF receptor 1) or the kinase (Ras‐mitogen‐activated protein kinase 1) resulted in a inhibition of single and double DNA strand‐break repair in the keratinocyte stem cells. Moreover, supplementing the progenitor cells with exogenous FGF2 activated their DNA repair. We propose that, apart from its well‐known role as a strong mitogen and prosurvival factor, FGF2 helps to maintain genomic integrity in stem cells by activating stress‐induced DNA repair. STEM CELLS 2010; 28:1639–1648.