FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21(Waf1) and p27(Kip1).
Signaling through fibroblast growth factor receptor one (FGFR1) is a known inducer of proliferation in both embryonic and human adult mesenchymal stem cells (hMSCs) and positively regulates maintenance of stem cell viability. Leveraging the mitogenic potential of FGF2/FGFR1 signaling in stem cells for therapeutic applications necessitates a mechanistic understanding of how this receptor stimulates cell cycle progression. Using small interfering RNA (siRNA) depletion, antibody-inhibition, and small molecule inhibition, we establish that FGFR1 activity is rate limiting for self-renewal of hMSCs. We show that FGFR1 promotes stem cell proliferation through multiple mechanisms that unite to antagonize cyclin-dependent kinase (CDK) inhibitors. FGFR1 not only stimulates c-Myc to suppress transcription of the CDK inhibitors p21(Waf1) and p27(Kip1), thus promoting cell cycle progression but also increases the activity of protein kinase B (AKT) and the level of S-phase kinase-associated protein 2 (Skp2), resulting in the nuclear exclusion and reduction of p21(Waf1). The in vivo importance of FGFR1 signaling for the control of proliferation in mesenchymal progenitor populations is underscored by defects in ventral mesoderm formation during development upon inhibition of its signaling. Collectively, these studies demonstrate that FGFR1 signaling mediates the continuation of MSC growth and establishes a receptor target for enhancing the expansion of mesenchymal progenitors while maintaining their multilineage potential.
Institute of Medical Biology, Glycotherapeutics Group, 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore, Singapore.
Christian
C
Dombrowski
Torben
T
Helledie
Ling
L
Ling
Martin
M
Grünert
Claire A
CA
Canning
C Michael
CM
Jones
James H
JH
Hui
Victor
V
Nurcombe
Andre J
AJ
van Wijnen
Simon M
SM
Cool
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D014982:Xenopus laevis
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
Adult stem cells; Cell cycle; Cell expansion; Fibroblast growth factor; Heparin-binding