The transcription program that is responsible for the pluripotency of human ESCs (hESCs) is believed to be comaintained by exogenous fibroblast growth factor-2 (FGF-2), which activates FGF receptors (FGFRs) and stimulates the mitogen-activated protein kinase (MAPK) pathway. However, the same pathway is stimulated by insulin receptors, insulin-like growth factor 1 receptors, and epidermal growth factor receptors. This mechanism is further complicated by intracrine FGF signals. Thus, the molecular mechanisms by which FGF-2 promotes the undifferentiated growth of hESCs are unclear. Here we show that, in undifferentiated hESCs, exogenous FGF-2 stimulated the expression of stem cell genes while suppressing cell death and apoptosis genes. Inhibition of autocrine FGF signaling caused upregulation of differentiation-related genes and downregulation of stem cell genes. Thus, exogenous FGF-2 reinforced the pluripotency maintenance program of intracrine FGF-2 signaling. Consistent with this hypothesis, expression of endogenous FGF-2 decreased during hESC differentiation and FGF-2 knockdown-induced hESC differentiation. In addition, FGF-2 signaling via FGFR2 activated MAPK kinase/extracellular signal-regulated kinase and AKT kinases, protected hESC from stress-induced cell death, and increased hESC adhesion and cloning efficiency. This stimulation of self-renewal, cell survival, and adhesion by exogenous and endogenous FGF-2 may synergize to maintain the undifferentiated growth of hESCs.

• MeSH
• Enzyme Activation MeSH
• Cell Adhesion drug effects   physiology   MeSH
• Cell Differentiation drug effects   physiology   MeSH
• Cell Line MeSH
• Cell Growth Processes drug effects   physiology   MeSH
• Down-Regulation MeSH
• Embryonic Stem Cells cytology   drug effects   metabolism   MeSH
• Gene Expression MeSH
• Fibroblast Growth Factor 2 genetics   metabolism   pharmacology   MeSH
• Phosphorylation MeSH
• Immunoblotting MeSH
• Humans MeSH
• Mitogen-Activated Protein Kinases metabolism   MeSH
• Oncogene Protein v-akt metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Receptor, Fibroblast Growth Factor, Type 2 metabolism   MeSH
• Signal Transduction MeSH
• Cell Survival drug effects   physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fibroblast Growth Factor 2 MeSH
• Mitogen-Activated Protein Kinases MeSH
• Oncogene Protein v-akt MeSH
• Receptor, Fibroblast Growth Factor, Type 2 MeSH