FGFR1 Signaling Stimulates Proliferation of Human Mesenchymal Stem Cells by Inhibiting the Cyclin-Dependent Kinase Inhibitors p21Waf1 and p27Kip1

Authors


  • Author contributions: C.D.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; T.H.: collection and/or assembly of data and data analysis and interpretation; L.L.: collection and/or assembly of data, manuscript writing, and administrative support; M.G. and C.A.C.: collection and/or assembly of data; C.M.J. and J.H.H.: provision of study materials, conception and design, and financial support; V.N.: conception and design, manuscript writing, and financial support; A.J.V.W.: conception and design, manuscript writing, final approval of manuscript, financial support; S.M.C.: conception and design, manuscript writing, final approval of manuscript, and financial support. C.D. and T.H. contributed equally to this manuscript.

Correspondence: Simon Cool, Ph.D., Institute of Medical Biology, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore. Telephone: +65-64070176; Fax: +1-507-284-5075 e-mail: simon.cool@imb.a-star.edu.sg; or Andre van Wijnen, Ph.D., Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, MedSci 3–69, Rochester, Minnesota 55905, USA. Telephone: +1-507-293-2105; Fax: +1-507-284-5075; e-mail: vanwijnen.andre@mayo.edu

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 p21Waf1. 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. Stem Cells 2013;31:2724–2736

Ancillary