title: Fibroblast Growth Factor 2 Regulates High Mobility Group A2 Expression in Human Bone Marrow-Derived Mesenchymal Stem Cells.
abstract: Mesenchymal stem cells (MSCs) are an excellent source for numerous cellular therapies due to their simple isolation, low immunogenicity, multipotent differentiation potential and regenerative secretion profile. However, over-expanded MSCs show decreased therapeutic efficacy. This shortcoming may be circumvented by identifying methods that promote self-renewal of MSCs in culture. HMGA2 is a DNA-binding protein that regulates self-renewal in multiple types of stem cells through chromatin remodeling, but its impact on human bone marrow-derived MSCs is not known. Using an isolation method to obtain pure MSCs within 9 days in culture, we show that expression of HMGA2 quickly decreases during early expansion of MSCs, while let-7 microRNAs (which repress HMGA2) are simultaneously increased. Remarkably, we demonstrate that FGF-2, a growth factor commonly used to promote self-renewal in MSCs, rapidly induces HMGA2 expression in a time- and concentration-dependent manner. The signaling pathway involves FGF-2 receptor 1 (FGFR1) and ERK1/2, but acts independent from let-7. By silencing HMGA2 using shRNAs, we demonstrate that HMGA2 is necessary for MSC proliferation. However, we also show that over-expression of HMGA2 does not increase cell proliferation, but rather abrogates the mitogenic effect of FGF-2, possibly through inhibition of FGFR1. In addition, using different methods to assess in vitro differentiation, we show that modulation of HMGA2 inhibits adipogenesis, but does not affect osteogenesis of MSCs. Altogether, our results show that HMGA2 expression is associated with highly proliferating MSCs, is tightly regulated by FGF-2, and is involved in both proliferation and adipogenesis of MSCs. J. Cell. Biochem. 117: 2128-2137, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Stem Cell Program, Department of Internal Medicine, University of California, Davis, California.
authors.forename: Stefanos
authors.initials: S
authors.lastname: Kalomoiris
authors.affiliation: Stem Cell Program, Department of Internal Medicine, University of California, Davis, California.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Cicchetto
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Lakatos
authors.affiliation: Stem Cell Program, Department of Internal Medicine, University of California, Davis, California.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Nolta
authors.affiliation: Stem Cell Program, Department of Internal Medicine, University of California, Davis, California.|Department of Cell Biology and Human Anatomy, University of California, Davis, California.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Fierro
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D025743:HMGA2 Protein / Q000096:biosynthesis*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism
chemical_list: D025743:HMGA2 Protein; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: BONE MARROW STROMAL CELLS; FIBROBLAST GROWTH FACTOR 2; HIGH MOBILITY GROUP A2; MESENCHYMAL STEM CELLS; SELF-RENEWAL