EGFR ligands drive multipotential stromal cells to produce multiple growth factors and cytokines via early growth response-1.
Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)-EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase-extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Svetoslava S
SS
Kerpedjieva
Duk Soo
DS
Kim
Dominique J
DJ
Barbeau
Kenichi
K
Tamama
D066258:Amphiregulin; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D066255:EGF Family of Proteins; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008024:Ligands; D034741:RNA, Small Interfering; C016658:phorbolol myristate acetate; C512478:EGFR protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate