FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1

Christian Dombrowski, Torben Helledie, Ling Ling, Martin Grünert, Claire A. Canning, C. Michael Jones, James H. Hui, Victor Nurcombe, Andre J van Wijnen, Simon M. Cool

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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 p21Waf1 and p27Kip1, 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.

Original languageEnglish (US)
Pages (from-to)2724-2736
Number of pages13
JournalStem Cells
Volume31
Issue number12
DOIs
StatePublished - Dec 2013

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Cyclin-Dependent Kinases
Mesenchymal Stromal Cells
Adult Stem Cells
Stem Cells
Cell Cycle
S-Phase Kinase-Associated Proteins
Fibroblast Growth Factor Receptors
Proto-Oncogene Proteins c-akt
Fibroblast Growth Factor 2
Mesoderm
Small Interfering RNA
Cell Survival
Maintenance
Cell Proliferation
Antibodies
Growth
Population
Therapeutics

Keywords

  • Adult stem cells
  • Cell cycle
  • Cell expansion
  • Fibroblast growth factor
  • Heparin-binding

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Dombrowski, C., Helledie, T., Ling, L., Grünert, M., Canning, C. A., Jones, C. M., ... Cool, S. M. (2013). FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1 Stem Cells, 31(12), 2724-2736. https://doi.org/10.1002/stem.1514

FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1 . / Dombrowski, Christian; Helledie, Torben; Ling, Ling; Grünert, Martin; Canning, Claire A.; Jones, C. Michael; Hui, James H.; Nurcombe, Victor; van Wijnen, Andre J; Cool, Simon M.

In: Stem Cells, Vol. 31, No. 12, 12.2013, p. 2724-2736.

Research output: Contribution to journalArticle

Dombrowski, C, Helledie, T, Ling, L, Grünert, M, Canning, CA, Jones, CM, Hui, JH, Nurcombe, V, van Wijnen, AJ & Cool, SM 2013, 'FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1 ', Stem Cells, vol. 31, no. 12, pp. 2724-2736. https://doi.org/10.1002/stem.1514
Dombrowski, Christian ; Helledie, Torben ; Ling, Ling ; Grünert, Martin ; Canning, Claire A. ; Jones, C. Michael ; Hui, James H. ; Nurcombe, Victor ; van Wijnen, Andre J ; Cool, Simon M. / FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1 In: Stem Cells. 2013 ; Vol. 31, No. 12. pp. 2724-2736.
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