A complex role for FGF-2 in self-renewal, survival, and adhesion of human embryonic stem cells.
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.
Eiselleova
Livia
L
Department of Biology, Faculty of Medicine University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Matulka
Kamil
K
Kriz
Vitezslav
V
Kunova
Michaela
M
Schmidtova
Zuzana
Z
Neradil
Jakub
J
Tichy
Boris
B
Dvorakova
Dana
D
Pospisilova
Sarka
S
Hampl
Ales
A
Dvorak
Petr
P
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D016222:Fibroblast Growth Factor 2; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases