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a Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
b Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
c Harvard School of Dental Medicine, Boston, Massachusetts, USA
Key Words. Mesenchymal stem cells • Mitogen-activated protein kinase • Phospholipase C • Signal transduction • Regenerative medicine • Adipogenesis • Osteogenesis • Ex vivo expansion
Correspondence: Alan Wells, M.D., DMSc., Department of Pathology, University of Pittsburgh, 3550 Terrace Street, 713 Scaife Hall, Pittsburgh, Pennsylvania 15261, USA. Telephone: 412-647-7813; Fax: 412-647-8567; e-mail: wellsa{at}upmc.edu
Received on April 18, 2005;
accepted for publication on September 2, 2005.
Bone marrow mesenchymal stem cells (BMMSCs) are pluripotent cells capable of differentiating into several cell types and are thus an attractive cell source for connective tissue engineering. A challenge in such a use is expansion and directed seeding in vitro, requiring proliferation and survival, and directed migration, respectively, prior to functional differentiation. The epidermal growth factor (EGF) receptor (EGFR) is the prototypal growth factor receptor and elicits these responses from a wide variety of stromal, epithelial, and endothelial cells. Ligands for this receptor are appealing for use in tissue engineering because they are relatively resistant to biological extremes and amenable to high-volume production. Therefore, we determined whether an EGFR ligand, EGF, could be used for ex vivo expansion of BMMSCs. EGF stimulated motility in rat and immortalized human BMMSCs. EGF-induced proliferation was observed in immortalized human BMMSCs but was not apparent in rat BMMSCs under our experimental conditions. EGF did not, however, rescue either type of BMMSC from apoptosis due to lack of serum. During our examination of key signaling intermediaries, EGF caused robust phosphorylation of extracellular signal-regulated protein kinase (ERK) and protein kinase B/akt (AKT) but only minimal phosphorylation of EGFR and phospholipase C-
in rat BMMSCs, whereas in the human BMMSCs these intermediaries were all strongly activated. EGF also induced robust ERK activation in primary porcine mesenchymal stem cells. EGF pretreatment or cotreatment did not interfere with secondarily induced differentiation of either type of BMMSC into adipogenic or osteogenic lineages. Platelet-derived growth factor (PDGF) effects were similar to but not additive with those elicited by EGF, with some quantitative differences; however, PDGF did interfere with the differentiation of these BMMSCs. These findings suggest that EGFR ligands could be used for ex vivo expansion and direction of BMMSCs.
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