Fibroblast growth factor-4 enhances proliferation of mouse embryonic stem cells via activation of c-Jun signaling

PLoS One. 2013 Aug 13;8(8):e71641. doi: 10.1371/journal.pone.0071641. eCollection 2013.

Abstract

Fibroblast growth factor-4 (FGF4) is expressed in embryonic stages and in adult tissues, where it plays critical roles in modulating multiple cellular functions. However, the exact roles of FGF4 on proliferation and differentiation of embryonic stem cells (ESCs) are not completely understood. Exogenous addition of FGF4 stimulated proliferation of mouse ESCs (mESCs), as proven by the increases in DNA synthesis and cell cycle regulatory protein induction. These increases were almost completely inhibited by pre-treating cells with anti-FGF4 antibody. FGF4 also activated c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) signaling, but not p38 kinase. Blockage of JNK signaling by SP600125 or by transfection with its specific siRNA significantly inhibited FGF4-stimulated cell proliferation through the suppression of c-Jun induction and activator protein-1 (AP-1) activity. However, ERK or p38 kinase inhibitor did not affect FGF4-stimulated proliferation in mESCs. FGF4 suppressed osteogenic differentiation of mESCs by inhibiting expression of transcription factors involved in bone formation. Further, exogenous FGF4 addition stimulated proliferation of human periodontal ligament stem cells (hPDLSCs) and bone marrow mesenchymal stem cells (BMMSCs) via activation of ERK signaling. FGF4 also augmented mineralization of hPDLSCs, but not of BMMSCs. Collectively, it is suggested that FGF4 triggers proliferation of stem cells by activating MAPK-mediated signaling, while it affects differently osteogenic differentiation according to the origins of stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Calcification, Physiologic / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 4 / antagonists & inhibitors
  • Fibroblast Growth Factor 4 / pharmacology*
  • Gene Expression Regulation / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteogenesis / drug effects
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction / drug effects*
  • Sp7 Transcription Factor
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • Cell Cycle Proteins
  • Core Binding Factor Alpha 1 Subunit
  • Fibroblast Growth Factor 4
  • Proto-Oncogene Proteins c-jun
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Transcription Factor AP-1
  • Transcription Factors
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases

Grants and funding

This research was supported by Basic Science Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0009123). This paper was in part supported by research funds of Chonbuk National University in 2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.