Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells.
Adipose tissue-derived stem cells offer tremendous potential for regenerative medicine. However, characterization of their self-renewal ability has not been performed yet, although it is a crucial feature for in vitro expansion of undifferentiated cells and in vivo maintenance of stem cell pools. We have undertaken the identification of molecular events that are involved in in vitro self-renewal of human multipotent adipose-derived stem (hMADS) cells from young donors, by assessing their proliferation rate, their ability to grow at the single-cell level (clonogenicity), and their differentiation potential. As hMADS cells are propagated in culture, cell morphology changes dramatically, concomitantly to a progressive decrease in proliferation, clonogenicity, and differentiation potential. This decrease is associated with a decrease in fibroblast growth factor 2 (FGF2) expression and can be circumvented by chronic treatment with exogenous FGF2. Moreover, analysis of FGF2 secretion revealed that it is exported to hMADS cell surface without being released into the culture medium, suggesting a strictly autocrine loop. Indeed, treatment of FGF2-expressing hMADS cells with PD173074, a specific FGF receptor inhibitor, decreases dramatically their clonogenicity and differentiation potential. Thus, hMADS cells express a functional autocrine FGF loop that allows maintenance of their self-renewal ability in vitro. Finally, inhibition of mitogen-activated protein kinase kinase 1 reduces the clonogenic potential of hMADS cells but does not affect their differentiation potential, indicating that the extracellular signal-related kinases 1/2 signaling pathway is partly involved in FGF2-mediated self-renewal. Together, our data clearly identify the key function of FGF2 in the maintenance of self-renewal of adipose tissue-derived stem cells.
Zaragosi
Laure-Emmanuelle
LE
Institut de Recherche, Signalisation, Biologie du Développement et Cander, UMR6543 Centre National de la Recerche Scientifique, Centre de Biochimie, Faculté des Sciences, Université Nice Sophia-Antiplis, Nice, France.
Ailhaud
Gérard
G
Dani
Christian
C
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D002070:Butadienes; D009570:Nitriles; C115711:PD 173074; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; C113580:U 0126; D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1